Acute Kidney Injury State of the art

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1 Acute Kidney Injury State of the art JM. Hougardy, MD, PhD Nephrology, Dialysis & Renal ULB Hôpital Erasme Joint SBN---BVN/BeSEDiM, 24th October 2013, UCL, Brussels The normal kidney % Res@ng cardiac output Regula@on of constant extracellular environment Maintenance of metabolic homeostasis Solute/water reabsorp@on Transport processes High energy requirements Greater intra---tubular concentra/ons of filtered toxicants High intra---cellular concentra/ons of toxicants/metabolites Metabolism/transport, role of microcircula/on 1

2 Do you said acute renal failure? 1200 «Acute kidney injury» (RIFLE or AKIN) Annual (n=) «Acute renal failure» (>35 definiions) Number of referenced publica@ons (Pubmed search, 21 Nov 2012 with «Acute Kidney Injury», Title/Abstract) AKI: more than ARF Acute renal failure (ARF) 1 st seen in Pubmed 1946 (1802 in lic.) AKI (Acute Kidney Injury) 2004 (ADQI) Semiology Histology (e)gfr (Serum) Plasma CreaInine Delay in diagnosis Edema, acidosis, uremia, hyperkaliemia, etc. Ofen (wrongly) associated with acute tubular necrosis Significantly decreased Variable increase Long (> h) afer injury Vary according defini@on May be absent Subtle modifica@ons may occur Not a criteria for AKI May be normal Consensual --- KDIGO 2012 Earlier, may be more earlier with future biomarkers? 2

3 Acute kidney injury Encompasses the spectrum of the renal injury From minor changes in markers of renal To requirement for renal replacement therapy (RRT) Perazella/Coca Nat Rev Nephrol 2013 Acute kidney injury Encompasses the spectrum of the renal injury From minor changes in markers of renal To requirement for renal replacement therapy (RRT) AKI is NOT ATN, nor is it renal failure encompasses both and also includes other, less severe Also include with impairment to physiological demand (may benefit from early Include injury a/o impairment 3

4 Conceptual model for AKI ACEi ARBs GFR Normal risk Damage GFR Kidney failure Death Iodinated contrast ag. hypovolemia sepsis Damage Incipient AKI Establishe d AKI Biomarkers /--- Crea@nine --- +/ Altered UO +/ AK injury & diseases? Is one of the number acute kidney diseases (AKD) Can occur +/--- other acute or chronic kidney diseases/disorders AKI is a subset of AKD CKD is a significant risk factor of AKI CKD AKD AKI CKD AKI AKD may occur without AKI (e.g. IgAN) AKI may remain AKD (eg. func@onal) Or predispose to CKD (JASN 2009;20: ) 4

5 How to define AKI? (2004) (2007) 48h afer event (not only admission) > days The consensus about AKI: win---win? Biomarkers (performances, design) Treatment evalua@on) +meaningful comparisons across studies 1 Prophylaxy Preven@on Research Consensual defini@on Diagnos@c work---up Therapeu@c aqtudes Rapid reac@ons (KDIGO 2012) Clinical tools Early detec@on of AKI 1 Cruz DN et al. Crit Care 2009;13:211 5

6 AKI---KDIGO (2012) Combined parts of RIFLE and AKIN, Capture AKI with increased sensiivity Less stringent requirements for in those with CKD any increase above 4.0 mg/dl Pediatric The cause of AKI should be determined whenever possible But! Only considers severity of injury (rise in scr or fall in UO) Does not consider: isolated hematuria, proteinuria, casts that could be markers of incipient AKD/AKI KDIGO 2012: staging AKI Staging of AKI Stage Serum creainine Urine output 1 baseline OR > 0.3 mg/dl increase < 0.5 ml/kg/hr for hrs baseline < 0.5 ml/kg/hr for > 12 hrs baseline OR Increase in scr to 4 mg/dl OR 3 RRT OR (<18 yrs: egfr<35 ml/min/1.73m 2 ) < 0.3 ml/kg/hr for > 24 hrs OR Anuria for > 12 hrs 6

7 +0.3 mg/dl in Cr? Are you kidding? Changes in Major (>2.0 mg/dl): rare (exc. ICU) Minor (> ): frequent ( %) Impacts: mortality, LOS, costs +0.3 mg/dl: mortality x mg/dl: mortality x6.5, LOS +3.5d, costs: Mechanisms? Volume overload, of uremic compounds, acidosis, electrolyte disorders, increased risk for anemia Ref. Chertow et al., Lassnig et al. egfr and AKI? All egfr formulas were evaluated in steady---state and are not adapted for acute J Am Soc Nephrol May;24(6): doi: /ASN Epub 2013 May 23. 7

8 «Baseline» creainine Not readily available % of cases 0 No standard defini@ons 1 «Back---calcula@on»(ADQI)? Consider a «fits---it---all» pcr value afer assump@on of premorbid egfr of 75 ml/min by MDRD Limited a R p i p s li k cab o il f ity b to e u in su g al clinical i p n ra a c p ce r < o s p u r b i s a ta t n l a y l propaogr@gonrehasvseivpere---(efxais@lsneg +CK)D 2,3 Risk of Overdiagnosis of AKI in CKD pa@ents The first---available Cr value following admission (AKIN)? Acceptable for stable pa@ents and elec@ve procedures (e.g. cardiac surgery, contrast---based interven@ons)? Community---acquired AKI Risk of misguided c C o re m a@ p ni l n a e m c a e y n ha c ve y alr ( e f a a dy l r s is e en - w ) ell above the true baseline by of hospital presenta@on > risk of overs@ma@on of the baseline Cr > underapprecia@on of true AKI 4 Best reflected by recent pcr values during past days 5 0 Nickolas JACC 2012;59: ; 1Gaiao S, Cruz DN. NDT 2010;25: , 2 Hsu CY et al. Kidney Int 2008;74: , 3 Khosla N et al cjasn 2009;4: , 4 Siew ED et al Kidney Int 2010;77:536, 5 Siew ED et al cjasn 2012;7: «Baseline» creainine remains unsolved Risk of bi---direc@onal misclassifica@on should be taken into considera@on when reading/interpre@ng the literature Cruz DN et al. Crit Care 2009;13:211 Improved methods to es@mate baseline Cr are needed ( ). We do not want to find ourselves ( ) with everyone using RIFLE/AKIN, but having 30 more different defini@ons of baseline crea@nine Gaiao S, DN Cruz, NDT 2010;25: «Base---line free» classifica@on systems (e.g. biomarker---based strategy)? 8

9 DuraIon of AKI? RIFLE, AKIN & KDIGO?Do not differenciate subtypes of AKI: pre---renal is probably less severe and is probably not to stage---1 associated mortality? Do not take account of of AKI! Several were started to validate duraion of AKI as a severity marker of AKI among several popula@ons: NSQIP cohort (Coca et al Kidney Int 2010) Cardiac surgery (Brown et al Ann Thorac Surg 2010) ICU (Uchino NDT 2010) DuraIon of AKI? NSQIP Cohort (n=35.302) Similar observa@ons: TRIBE---AKI consor@um ; Uchino NDT 2010;25:1833 9

10 KDIGO 2012: staging AKI Staging of AKI Stage Serum creainine Urine output 1 baseline OR > 0.3 mg/dl increase < 0.5 ml/kg/hr for hrs baseline < 0.5 ml/kg/hr for > 12 hrs baseline OR Increase in scr to 4 mg/dl OR 3 RRT OR (<18 yrs: egfr<35 ml/min/1.73m 2 ) < 0.3 ml/kg/hr for > 24 hrs OR Anuria for > 12 hrs Urine output The most rapid and cheapest bedside test for kidney func@on AKI may be diagnosed from UO in as licle as 2---3hrs! The oldest marker for ARF/AKI (Galen 200 C.E.) No baseline required RIFLE, AKIN, KDIGO Dura@on and UO were defined by consensus not physiology 10

11 UO on an intensive care unit: case---control study 1 Cases: junior doctors (n=18) & Controls: pa@ents in the unit clerked by those doctors ; Oliguria <0.5 ml/kg/h over > 6h Results: 22% of doctors were classed as «oliguric» and «RIFLE R» & 1% «RIFLE I» Doctors were twice as likely to be oliguric (P 0.03) Mortality among doctors was astonishingly low (0% vs % for R/I) Conclusion: Managing our own fluid balance is difficult More than managing it in our pa@ents More than auto---appendicectomy, (successful in 100% of published acempts) We should drink more water 1 Solomon AW et al. BMJ 2010;341:c6761, Christmas 2010: The Lives of the Doctors Urine output criteria UO might be a «sofer» marker of AKI Accross studies, consistently classifies more pa@ents as AKI Less robust literature, controversial results about predic@on of mortality 0.5 ml/kg/h for 6---h (averaging) for AKI has not been prospec@vely validated In the ICU 1, a 6h UO <0.3 ml/kg/h was: best associated with mortality and dialysis (prospec@ve) Indepently predic@ve of both hospital and 1---yr mortality 0.5 ml/kg/h is probably «too liberal» for AKI defini@on in the ICU A. Ralib et al. Crit Care 2013;17:R112 (FLAKI data, New Zealand) 11

12 Go with the flow to monitor AKI! Oliguria could be observed in % AKI: not specific to a given cause of AKI, prognos@c value <400 ml/day ; anuria < 100 ml/day <0.5 ml/kg/h (KDIGO) Simple but ofen cumbersome Placement of urinary catheter may not be indicated Bladder KT could be an op@on but Nurse workload: up to min/h ( min/8h shif), error in es@ma@ng volume ( %) or in ( %) 1 Interest of electronic urinometer for high---risk pa@ents (URINFO 2000) 1 Ask the pa@ents to collaborate for urine collec@on 1. Bar---Lavie Y. et al, Poster ESICM 2009; R94 AKI in the Emergency room 12

13 AKI in the ER? Few specific studies in the ER, mostly controlled seqngs : ICU (sepsis), cardiac surgery, contrast administra@on, (hospitalized---acquired) AKI in the ED: «Community---acquired» AKI Not a controlled seqng Other ae@ologies: nephrotoxicity, ischemic---injury, HRS,etc. +/ % of adults admiced to hospital Min % < volume deple@on (absence of nephron damage) As many as 90% of cases: poten@ally reversible cause Most AKI pa@ents are admiced with AKI but not iden@fied as having AKI on admission 1 Waikar SS et al cjasn 2008;3: ; 2 Ali T al JASN 2007;18: ; 3 Hsu CY et al Kidney Int 2007;72: Rather a catastrophic reality NCEPOD 2009: Adding Insult to Injury [hjp:// ] Other deficiencies: failure in AKI preven@on, recogni@on, therapy access to specialist services 13

14 Are we able to detect AKI earlier? BIOMARKERS OF AKI A long story short: The most promising AKI biomarkers in the ED NGAL: neutrophil gela@nase---associated lipocalin KIM---1: kidney injury molecule---1 IL---18: interleukin 18 L---FABP: Liver---Facy acid binding protein CysC: cysta@n C Diagnos@c and prognos@c performance has been evaluated Only single---center studies Selected clinical seqngs and selected subtypes of AKI 14

15 NGAL Experimental data NGAL is expressed: Tubular cells (BAL, macula densa, TC) Limited to ischemic area Correlated to lesion severity Produced by suffering cells Is not produced in case of AKI Paragas N, Qiu A, Zhang Q, Samstein B, Deng S---X, Schmidt---Oc KM, et al. Nat Med 2011;17: External validity? Krawczeski CD et al. JACC 2011;58:

16 NGAL & paients N Sample Cut---off Se Sp AUC Comments Zapitelli et al 140 U Pediatric (neonat), ICU Wheeler et al 143 P Pediatric (<10 yrs), sepsis Du et al 252 U Pediatric (<15 yrs), ED Nickolas et al. 635 U 130 µg/g No increase in func@onal AKI Aghe et al 91 P 140 ng/ml CHF Bashaw et al 83 U 230 ng/ml ICU, sepsis vs not (decr AUC in sepsis) Constan@n et al 88 P 155 ng/ml ICU Shapim et al 661 P 150 ng/ml Sepsis Endre et al 58 U 41 ng/mmol ICU Singer et al 141 U ED, hospit. For AKI Nickolas et 1635 U 104 ng/ml Specific to ED Soto K et al 616 P 146 ng/ml Specific to ED, AKIN 1 Soto K et al 616 P 174 ng/ml Specific to ED, AKIN 2+ Nickolas et al JACC 2012 ;59:246 1 Soto K et al cjas N Sept 2013 epub Rev iewed in Gagneux ---Brunan A et al. Nephrol Therap. 2012;8: Incidence of AKI in the ED Nickolas et al JACC 2012;59:246 (n=1635) 6% Intrinsic AKI 25% 16% Func@onal AKI Stable CKD RIFLE+, >3days, s@mulus inducing iaki Hypotension (34%), urinary obstruc@on (29%), sepsis (22%), GN/vasculi@s (6%), HRS(2%), rhabdomyolysis (2%) Strongly associated with adverse in---hospital outcomes 9% Normal renal fun c@on Uncertain diagno sis 45% 16

17 DiagnosIc strategy for every paients?* Incipient AKI? Established AKI? In---hospital mortality, RRT ungal displayed a closer associa@on with severity and dura@on of AKI ungal & ukim---1 were the most accurate predictors of subsequent clinical events No benefit from NGAL/KIM---1 associa@on DiagnosIc strategy for every paients?* * Admiced in the ED and subsequently hospitalized for > 24h. In line with Soto K et al. cjasn Sept 2013 Epub 17

18 Cheaper biomarker? Urine sediment score of 2 (> 6 renal tubular epithelial cells/highpower field) Urine sediment score of 2 (> 6 granular casts/low-power field) Clin J Am Soc Nephrol 7: ccc ccc, doi: /CJN Managing AKI in 2013 «Bejer safe than sorry» Few therapies are available to prevent or reverse most common forms of hospital---acquired AKI Lack of ability to prevent/reverse AKI Heterogeneous nature of renal injury Limited effec@ve interven@ons available Ofed marked delay in from renal insult to ini@al diagnosis of AKI Late interven@ons are unlikely to reverse structural injury that has developed 18

19 Managing AKI Relieving urological obstrucion Pharmacological management No loop to «treat» AKI, only for fluid overload or oedema Do not offer «low---dose» dopamine to «treat» AKI NICE Managing AKI Reffering to nephrology, discuss For difficult cases (e.g. RRT, suspected GN), unclear AKI, transplant, When egfr is <45 ml/min in who have recovered from AKI Proteinuria, hematuria NICE 19

20 Take---home messages «AKI oxen occurs in people under the care of healthcare professionals other than nephrologists», awareness is and the ignorance of AKI is adding insult to injury. Is frequent (>15%) in the Emergency room but 3 yrs ago Only 50% of AKI received good care (UK) Frequently undetected AKI---KDIGO classifica@on system now define AKI into 3 stages Based on severity, sensi@ve (as pcr can do ) Easy but s@ll present weaknesses (baseline pcr, UO, dura@on, incipient AKI) Take---home messages Early and systema@c recogni@on of AKI is required Small pcr changes, huge consequences (RRT, CKD, mortality) Go to the flow: follow urinary output Place of biomarkers remains undefined, but will be clarified in the next future (? Detec@on of incipient AKI, transient AKI) May lead to a becer renal prognosis 1,2 Doctors should drink more (water) 1 Kohle NB et al 2008;12:S2 ; 2 Kiers HD et al J Crit Care 2010;25:563 20