Acute  Kidney  Injury  

Dr  S  Mathavakkannan  Consultant  Nephrologist  

Scope  

1. Defini@on  2. Epidemiology  3. Physiology  4. Markers  of  Injury  5. Survival  6. Treatment  7. AKI  Preven@on  

Defini@on(s):  1.  ADQI  

1.  RIFLE  Criteria      Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group; 2004

•  Risk (Class R) •  Injury (Class I) •  Failure (Class F)  

   

Stra%fica%on  Based  on  RIFLE  

RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis

Hoste et al ; Critical Care 2006 (10) R73

Outcomes of all Patients based on RIFLE Class

Survival: Based on RIFLE Categorisation

Defini@on(s):  

1.  ADQI  1.  RIFLE  Criteria  

 2.  AKIN  

1.  Modified  RIFLE  Criteria  1.  Serum  crea@nine  rises  by  ≥  26µmol/L  from  the  baseline  value  within  48  

hours  2.  Serum  crea@nine  rises  ≥  1.5  fold  from  the  baseline  value  3.  urine  output  is  <  0.5ml/kg/hr  for  >6  consecu@ve  hours      

Ques@ons  in  AKI  

Incidence  of  AKI  1.  US:  

1.  1%    2.  7.1%  

2.  UK:  1.  172pmp  2.  486-­‐630pmp  3.  AKI-­‐RRT:  20-­‐203pmp  

3.  Cri@cal  Care:    1.  5-­‐20%  of  pa@ents  develop  AKI  2.  4.9%  of  admissions  require  RRT  3.  AKI  accounts  10%  Hospital  Days  

4.  AKI  in  Hospital:  1.  10-­‐80%  mortality  2.  Uncomplicted  AKI:  Mortality  of  10%  3.  AKI  in  mul@-­‐organ  failure:  50%  4.  AKI  requiring  RRT  in  Mul@-­‐organ  failure  :  80%  

Study  overview  

Proposed  by  the  Renal  Associa4on    •  Prevalent  and  serious  problem  amongst  hospitalised  pa@ents  

•  All  hospital  pa@ents,  regardless  of  specialty,  are  at  risk  of  AKI  

•  It  is  unknown  to  what  degree  strategies  to  reduce  the  risk  of  AKI  are  implemented  

Primary  aim  

 To  examine  the  process  of  care  of  pa@ents  

who  died  in  hospital  with  AKI,  in  order  to  

iden@fy  remediable  factors  in  the  care  

received  by  these  pa@ents  

Data  returns  

Key  findings  

•  Only  50%  of  AKI  care  considered  good  •  Poor  assessment  of  risk  factors  •  Unacceptable  delay  in  recogni@on  of  post-­‐admission  in  AKI  in  43%  

•  22  pa@ents  died  with  a  primary  diagnosis  of  post-­‐admission  AKI  which  was  predictable  and  avoidable  

•  Complica@ons  missed  (13%),  avoidable  (17%)  or  badly  managed  (22%)  

NCEPOD  Report  2009  

Comprehensive  Assessment  in  AKI  

3.  poten@al  causes  for  AKI  including    3.  reduced  fluid  intake    4.  increased  fluid  losses    5.  urinary  tract  symptoms    6.  recent  drug  inges@on    7.  sepsis    

4.  systemic  clinical  features    4.  fever    5.  rash    6.  joint  pains  

1. pa@ent  notes        2. AKI  risk  factors    

1.  age  >  75  yrs    2.  chronic  kidney  disease  

(CKD,  eGFR  <  60  mls/min/1.73m2)    

3.  Cardiac  failure    4.  Atherosclero@c  peripheral  

vascular  disease    5.  Liver  disease    6.  Diabetes  mellitus    7.  Nephrotoxic  medica@ons  

Comprehensive  Assessment  in  AKI  •  general    

–  rash    –  uvei@s    –  joint  swelling    

•  assessment  of  volume  status    –  core  temperature    –  peripheral  perfusion    –  heart  rate    –  blood  pressure    –  jugular  venous  pressure    

•  signs  of  renovascular  disease    –  audible  bruits    –  impalpable  peripheral  pulses    

•  abdominal  examina@on    –  palpable  bladder    

 

Inves@ga@ons:AKI  •  biochemistry    

–  Urea  and  electrolytes    •  haematology    

–  FBC    •  urinalysis  (±  microscopy)    •  microbiology    

–  urine  culture  (if  infec@on  is  suspected)    

–  blood  culture  (if  infec@on  is  suspected)    

•  renal  immunology    •  urinary  biochemistry    

–  electrolytes    –  osmolality    

•  ECG    •  chest  x-­‐ray    •  abdominal  x-­‐ray    •  renal  tract  ultrasound  

(within  24hrs  if  obstruc@on  suspected)  

•  kidney  biopsy    

Measurement  of  Crea%nine  

1. Poor  Biomarker  1. Jaffe  Reac@on  (1886)  2. Inter-­‐laboratory  varia@ons  and  analy@cal  interference  

3. Interference  1. Protein,  glucose,  ascorbate,  pyurvate,  cephalosporins  

2. Bilirubin  4. Enzyma@c  Assays  

1. Crea@ninase,  cre@nase,  sarcosine  oxidase  5. Calibra@on  against  IDMS  

Urine  Microscopy  

•  Proteinuria  (3+  or  >)  •  Haematuria  •  Lucocyturia  •  Eosinophiluria  •  Crystalluria  

–  EG  –  TLS  –  S,  AcyC,  IndinV,  TriamT,  Cathar@cs  

•  Myoglobinuria  

Urine  Electrolyte  Es@ma@on  

1. FENa  2. FEUrea  3. Urinary  Sodium  Excre@on  4. Free  water  clearence  5. Crea@nine  Clearence  6. Blood  Urea:Crea@nine  Ra@os  

1. Pre-­‐Renal  Azotemia    

2. ATN  3. Hepatorenal  Syndrome  

Biomarkers  of  AKI  

1. NGAL  2. KIM-­‐1  3. Cysta@n  C  4. IL-­‐8  5. NAG  6. L-­‐FABP  

Urinary  biomarkers  for  acute  kidney  injury  (AKI)  evaluated  in  at  least  2  human  studies  (Belcher  et  al;  AJKD;  March  2011)  

NGAL:  U@lity  in  Pre-­‐Renal  vs  AKI  Scenario  Singer  et  al;  KI  16  March  2011  

AKI-­‐Preven@ve  Strategies  

•  Major  Surgery  •  Sepsis:  SIRS  v  CARS;  EGDT;  Volume  and  Pressor  support;  euglycemia;  Low  Tidal  Vol  

•  CI-­‐AKI  •  Rhabdomyolysis    

AKI:  Preven@on  Strategies  Contrast  Induced  AKI  (CI-­‐AKI)    

 Parameter   Number  Number  in  Total   n=12;  1854  Preven@on  of  CI-­‐AKI  using  bicarbonate   n  =  12;  1652;  OR  0.46  (0.28-­‐0.82)  Need  for  RRT   n=9;  1215;  OR  0.5  Survival   n=11;  1640;  OR  0.51  Bicarbonate  use  in  CCF   No  difference  in  Survival;  no  excessive  

LVF  episodes  

Compare with REMEDIAL (NS+NAC v NaHCO3+NAC v NAC+Vit C+NS

Hoste et al AJKD 2009

Brer et al JASN

Contrast  Induced  AKI  (CI-­‐AKI)    

Contrast  Induced  AKI  (CI-­‐AKI)    

Flowchart of meta-analysis.

Brar S S et al. CJASN 2009;4:1584-1592

©2009 by American Society of Nephrology

Forest plot of randomized trials meeting inclusion criteria.

Brar S S et al. CJASN 2009;4:1584-1592

©2009 by American Society of Nephrology

AKI-­‐  Rhabdomyolysis  

Factors  1.  Trauma  2.  Burns  3.  Compartment  Syndrome  4.  Drugs  

1.  Sta@ns  2.  Coccaine  3.  Ecstasy  

Management  1.  Volume  Assessment  2.  Aggressive  hydra@on  3.  Alkalinisa@on  

1.  UO  100ml/hr  2.  Urine  pH>6.5  

General    Management  

1. Fluid  Resuscita@on  

1. Crystalloid  vs  Colloid  2. Oliguric  vs  Non-­‐Oliguric  AKI  

 2. Pharmacological  Therapy  

1. Frusemide:    2. Dopamine  3. Fenoldopam  4. ANP    

AKI-­‐General  Management:  Fluid  Resuscita@on  and  Euglycemia  

N  Engl  J  Med  2008;358:125-­‐39.  Intensive  Insulin  Therapy  and  Pentastarch  Resuscita@on  in  Severe  Sepsis  

AKI-­‐General  Management:  Role  of  Frusemide  Meta-­‐analysis  of  frusemide  to  prevent  or  treat  acute  renal  failure  

Ho  and  Sheridan  BMJ  2006  333;  7565  pp445  

Effect of frusemide on in-hospital mortality and proportion of patients requiring renal replacement therapy or dialysis.

Ho

K M

, Sh

erid

an D

J B

MJ

2006

;333

:420

Number of dialysis sessions required after frusemide or control treatments.

Ho K M , Sheridan D J BMJ 2006;333:420

©2006 by British Medical Journal Publishing Group

Proportion of patients remaining oliguric (urine output <500 ml/day) after frusemide or control treatments and those mentioning tinnitus or deafness.

Ho K M , Sheridan D J BMJ 2006;333:420

©2006 by British Medical Journal Publishing Group

AKI-­‐Pharmacological  Op@ons:  Fenoldopam  Beneficial  Impact  of  Fenoldopam  in  Cri%cally  Ill  Pa%ents  With  or  at  Risk  for  Acute  Renal  Failure:  A  Meta-­‐Analysis  of  Randomized  Clinical  Trials  Landoni  et  al;  AJKD  2007  

Parameter   Results  RCTs  in  Meta-­‐analysis   16  Number  of  pa@ents   1290  Risk  for  AKI   OR  0.43  Risk  of  Death   0.64  RRT  Requirement   OR  0.54  Hypotension   Frequency  in  Fenoldopam  group  not  

higher  ICU  Stay   -­‐0.61  

1.  Dopamine  A  1  Receptor  agonist  2.  Short  ac@ng  3.  Decreases  SVR  4.  Increases  both  cor@cal  and  medullary  blood  flow  

AKI-­‐Pharmacological  Op@ons:  ANP  

CJASN 2009; Nigwekar et al; 19 Trials 1861 patients

AKI-­‐General  Management  :  Nutri@on  

1.  Calories:  25-­‐35kcal/kg/day  2.  Amino  acids:  1.7g/kg/day  

3.  Die@cian  Input  within  24  hours  4.  Supplement  water  soluble  Vitamins  if  receiving  RRT  

5.  Treat  Hyperglycemia  Cau@ously  

6.  Consider  Selenium  

7.  Vit  C  supplementa@on  not  necessary    

8.  Vit  K  levels  may  be  elevated  

9.  Enteral  route  vastly  superior  10.   Electrolyte  disturbances  to  be  treated  as  required  

AKI-­‐General  Principles:  Place  of  Care  

•  Most  AKI  outside  Renal  Unit  •  Cri@cal  Factors  

–  +  or  –  non-­‐renal  organ  failure  –  Requirement  for  RRT  –  Renal  Specialist  Input  

•  Key  Interfaces  –  Cri@cal  care  outreach  –  Acute  renal  outreach  –  Specialist  renal/ICU  Interface  

•  Avoiding  deficiencies  in  ini@al  assessment  and  management  –  Physiological  Early  Warning  Scores  (MEWS/PARA  scoring)  –  Educa@on  –  Wrisen  guidelines  –  Senior  Specialist  Renal  Input  

AKI-­‐General  Principles:  Place  of  Care  

1.  Pa@ent  flow  from  cri@cal  care  to  renal  services:  a  year-­‐long  survey  in  a  cri@cal  care  network      (Wright  et  al  QJM  Aug  2008)  1.  219/527  pa@ents  survived  2.  Incidence  of  RRT  in  ICU  234  pmp/year  3.  Dura@on  of  RRT  in  ICU:  4  DAYS  4.  127/219  required  renal  support  outside  ICU  5.  74/129  were  provided  RRT  in  ICU  as  for  single  organ  failure  6.  113  ICU  days  u@lised  to  provide  this  support  

 2.  Kanagasundaram  NS,  Jones  KE.  Transfer  of  pa@ents  with  acute  kidney  injury  to  specialist  

renal    services-­‐-­‐physiological  early-­‐warning  systems,  applied  prior  to  transfer  from  outside  hospitals,  can    iden@fy  those  at  risk  of  deteriora@on.  QJM  2008;101:249-­‐250  •  SOFA  Score  to  assess  need  for  escala@on  

Suppor@ve  Management  in  AKI  Principles    

ü Volume  ü Acid-­‐base,  electrolytes  ü Nutri@on  ü Adequate  medica@on  dosing  

if  fails……  

RRT  

CRRT  vs  

IHD  

 Hybrid  Therapies  

Which  

When  

How  much  

Dialysis  therapies  

CVVHDF  AN69    membrane  100-­‐180ml/min  blood  flow  Heparin  or  no  an@coagula@on  

IHD  F50/60/80  Dialysers  150-­‐350ml/min  UF  250-­‐1000ml/h  3-­‐4  hours  

Story  of  beser  haemodynamic  stability  in  CRRT  vs  IHD          

Authors/Setting n Outcome ITU/1993/Davenport et al 32 combined AKI/hepatic

failure Intermittent vs CAVH/CAVHD 35 vs 25 treatments Increased ICP, decreased CO, decreased DO2

Van der Scheuren 1996 N=11 IHD increases systemic O2 consumption

Heering 1997 N=33 Cytokine removal with CVVH, improvement in CV haemodynamics

Misset 1996 N=27 CAVH vs HD; MAP changes similar in both groups

John and Griesbach 2001 N=30 (20 cvvh 10 hd) CVVH vs HD in sepsis; drop in HR, slight increase BP, splanchnic perfusion parameters unchanged

Kumar 2000 N=42 (25 EDD, 17 CVVH) 367 vs 117 treatment days, 7.5 vs 19.5 hours,

Kielstein JT N= 39, (CVVH 19, EDD 20) Earlier correction of acidosis, less heparin

Evidence  

NephSAP  September  2007  

Uehlinger  et  al  NDT  2005    Hypothesis:  CVVHD  beser      

N 125 Definition of AKI Creatinine >350, UO <20ml/h CVVHDF 70 IHD 55 Matching Demographics

Cause of AKI Severity of illness

Catecholamine use (75% overall) Identical in both arms Ventilation (75%) Identical in both arms ICU Mortality 34% vs 38% In hospital mortality 47% vs 51% Duration of RRT Identical Renal recovery 97% (1 in each group HD dependant)

in-­‐hospital  mortality  

length  of  hospital  stay  

Recovery  of  renal  func@on  

Blood  pressure  and  dura@on  of  modali@es  during  ICU  stay  

CVVHDF  vs  IHD  

Hemodiafe  (Vinsonneau  et  al,  The  Lancet  29th  July  2006)  

Eligibility:  AKI    crea@nine  >350;  urea  >36;  UO  <200ml/16h;  need  for  RRT  

Survival:  32.6%  vs  31.5%    IHD  survival  improved  through  trial  period  ?  CVVHDF  dose  inadequate  

Flow chart of the SHARF 4 study.

Lins R L et al. Nephrol. Dial. Transplant. 2009;24:512-518

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Preference  of  one  modality  over  another    q         IHD  modality  of  choice  for  managing  AKI  in  ICU  (Mehta  et  al)    

q         Local  preferences;    >97%  of  treatments  for  AKI  in  Australia  are  CRRT  

q         Haemodynamic  stability  governs  choice  of  therapy    

q         Con@nuous  removal  of  inflammatory  cytokines  beser  (?)  

q         Blood  membrane  contact  is  pro-­‐inflammatory        

Parameter CRRT IHD Geography Europe/Australia/SE Asia US/Canada ? Anticoagulation - + Therapeutic agents - + Nutrition - + Volume management ? more error prone easier Dialysate Less standardised across

regions simpler

Haemodynamic stability + (perceived) - Training Personnel intensive Relatively easier Ease of dialysis dose delivery

? - +

Convective clearence + BUT is it useful? _ Inflammatory cascade Dubious value None, may be less pro-

inflammatory as blood-membrane contact less

Cost - +

AKI-­‐  RRT  :  Equipment  

1.  Dialyser:  Synthe@c  or  Modified  Cellulosaic  2.  Bicarbonate  buffer  3. Microbiological  Integrity  of  Dialysate  4.  An@coagula@on  

1.  Heparin  vs  Citrate  2.  Prostacycline  3.  Saline  Flushes  4.  Choice  if  HIT  

1.  Danaproid/Fondaparineux  2.  Hirudin/Lepirudin  3.  Argotroban  4.  Nafamostat  

AKI-­‐  Dose  of  RRT  Kt/V  ~  1.2  URR  >  65%    

Evidence:  

1.  Veteran  Affairs/Na@onal  Ins@tute  of  Health  Acute  Renal  Failure  Trial  Network  2.  Randomised  Evalua@on  of  Normal  Versus  Augmented  Level  Renal  Replacement  

Therapy  (RENAL)  

How  much?    Ronco  et  al      Lancet    July  2000        Efficacy  of  three  different  doses  of  CVVH  

Intensity  of  Renal  Support  in  Cri%cally  Ill  Pa%ents  with  Acute  Kidney  Injury    

Intensity  of  Renal  Support  in  Cri%cally  Ill  Pa%ents  with  Acute  Kidney  Injury  

 

•  Intense  vs  Conven@onal  –  IHD/SLED  6  @mes/week  – CVVH  at  35ml/kg/hour    

Mortality  at  60  days  

RENAL  Study  Design  

RENAL:  Outcome  Summary  

AKI-­‐  When  to  Start  RRT  

Era Number Criteria 1960s/1970s/1980s 3 BUN 90-100mg/dl 1990s At least 2 of importance

n=100; higher survival in early initiation n= 64, Cardiac ITU, 22 vs 43:: early/late

<60 BUN group vs >60 8 hr oliguria / >84mg/dl

PICARD n=243 Survival 80 & 65 (early) 75 & 59 (late) RR 1.85 (co-variate adj) RR 2.07 (propensity sco)

<76mg/dl vs >76mg/dl

BUT  Urea  cannot  be  a  surrogate  for  dura@on  of  AKI    AND    spontaneous  recovery    or  death  without  RRT  

AKI-­‐  When  to  Start  RRT    •  Early  start  a  ‘good  idea’  

•  How  early  is  early  –  Perhaps  Stage  3  of  AKIN  

•  Balance  Early  start  with  – Morbidity  associated  with  RRT  –  ?  Delays  recovery  from  AKI  – Many  pa@ents  pull  back  from  brink  with  suppor@ve  therapy  

– Urea  of  28mmol/L  a  cut  off?  21.5mmol/l?  UO  <100ml/8hr  

PICARD  Study  (  Cho  et  al  JASN  2006)    Observa@onal  study  CRRT  vs  IHD  Feb    (1999-­‐Aug  2001)  (n=398,  206  CRRT,  198  IHD)  AKI  defini@on:      q     Increase  in  serum  crea@nine  by  >44μmol/L  from  baseline,  if  baseline    <132μmol/L  q         Increase    in  serum  crea@nine  by  >88μmol/L  if  baseline    132<B<440  q     Baseline  CKD  eGFR<30ml/min  

Who got what?

CRRT IHD

Respiratory organ failure Fluid overload

Older No PA monitoring Higher BUN and creatinine Non-white population Higher SBP

AKI-­‐  Timing  of  RRT  

•  Timing  of  renal  replacement  therapy  and  clinical  outcomes  in  cri%cally  ill  pa%ents  with  severe  acute  kidney  injury  Beginning  and  Ending  Suppor@ve  Therapy  for  the  Kidney  (BEST  Kidney)      Bagshaw  et  al;  JoCC  March  2009    

 Parameter   Results  Type   Mul@centre,  23  countries,  52  ICUs,  1238  

pa@ents  Criteria   Early  vs  Late  Factors:  Urea  <24.2  vs  >24.2  Crea@nine  <309  vs  >309  ICU  Stay:  <2,  3-­‐5,  >5  

 OR  0.92/1.25  (63.4  VS  61.4%)  OR  0.46/0.51  (53.4  vs  71.3)  72.8  vs  62.3  vs  59  

AKI-­‐Educa@on