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Perioperative  Acute Kidney Injury Biomarkers, Physicians, and the Surgical Abdomen Dr. Andrew Ferguson Department of Anae...
Disclosures <ul><li>No conflicts of interest to declare </li></ul>
Outline <ul><li>Why AKI matters to us </li></ul><ul><li>Diagnostic and staging criteria for AKI </li></ul><ul><li>AKI risk...
Perioperative AKI is  NEVER  benign!
“ Predictable and avoidable AKI should never occur ” “ Post-operative AKI is avoidable in the elderly and  should not occu...
How do we diagnose & stage AKI? Cruz DN  et al.  Critical Care 2009;  13 : 211  
The grim reality of real world AKI <ul><li>In 222 non-ICU AKI patients requiring RRT… </li></ul><ul><li>29%   of patients ...
All grades of AKI matter! Cruz DN,  et al.  Critical Care 2009;  13 : 211 Ricci Z,  et al.   Kidney International 2008;  7...
Scoring Perioperative AKI Risk <ul><li>Age > 56 years </li></ul><ul><li>Male gender </li></ul><ul><li>Active CHF </li></ul...
Incidence - emergency surgery  N = 61, mean age 75, unpublished audit data
Incidence – elective surgery 1.  Thakar CV,  et al.  Clin J Am Soc Nephrol   2007 ;  2 : 426-430  2.  Kheterpal S,  et al....
Early diagnosis – the creatinine issue <ul><li>Variation with muscle mass & age etc. </li></ul><ul><li>Insensitive to rapi...
Biomarkers – the renal crystal ball?
Renal biomarker candidates <ul><li>Kidney injury molecule 1 (KIM-1) </li></ul><ul><li>Cystatin C </li></ul><ul><li>Interle...
NGAL - what is it? <ul><li>25kDa protein up-regulated in renal injury </li></ul><ul><li>Present in urine and plasma in AKI...
Biomarker time-course Time (hours) 0  3-6  24  48 NGAL KIM - 1 Cystatin C Creatinine McIlroy DR, Wagener G, Lee HT.  Anest...
NGAL and subclinical AKI <ul><li>NGAL rise only = similar outcomes to NGAL & creatinine rise </li></ul><ul><li>Retrospecti...
Biomarkers - unresolved issues <ul><li>Bedside vs. laboratory testing </li></ul><ul><li>Lack of  “real-world” assay valida...
Challenges in perioperative AKI Needs surgery NOW ! Can we keep up?
AKI Triggers & Perpetuators
AKI hurts other organ systems Grams ME, Rabb H. Kidney International 2011; advance online publication, 3 August 2011
General management <ul><li>Optimise haemodynamics </li></ul><ul><ul><ul><li>Appropriate fluid challenges </li></ul></ul></...
Problem areas - fluid overload <ul><li>Fluids do not reverse vasodilatory hypotension </li></ul><ul><li>Associated with po...
Fluid overload & adverse outcome 1  Grams ME,  et al.  Clin J Am Soc Nephrol 2011;  6 : 966-973 2  Boyd JH,  et al.  Crit ...
Fluid overload causes tissue oedema Prowle JR,  et al.  Nat Rev Nephrol 2010;  6 : 107-115 Cerebral Altered mental status ...
Fluid overload worsens tissue perfusion <ul><li>Shedding of  endothelial glycocalyx </li></ul><ul><ul><ul><li>Triggered by...
Microvascular responses to fluid <ul><li>Differs from the macro-haemodynamic response </li></ul><ul><li>Improvement in CO ...
Intra-abdominal hypertension <ul><li>Normal  I ntra- A bdominal  P ressure < 7 mmHg </li></ul><ul><li>Normal  A bdominal  ...
So what should we do? <ul><li>THINK  before fluids and  MONITOR  after </li></ul><ul><li>Early fluid resuscitation  is  ap...
Take-home points <ul><li>Any   degree of AKI = worse outcome </li></ul><ul><li>Risk recognition and tailored journey </li>...
<ul><ul><li>“ Poison is in everything,  </li></ul></ul><ul><ul><li>and no thing is without poison.  </li></ul></ul><ul><ul...
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Perioperative acute kidney injury

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  1. 1. Perioperative Acute Kidney Injury Biomarkers, Physicians, and the Surgical Abdomen Dr. Andrew Ferguson Department of Anaesthetics & Intensive Care Medicine Craigavon Area Hospital
  2. 2. Disclosures <ul><li>No conflicts of interest to declare </li></ul>
  3. 3. Outline <ul><li>Why AKI matters to us </li></ul><ul><li>Diagnostic and staging criteria for AKI </li></ul><ul><li>AKI risk factors in perioperative patients </li></ul><ul><li>Novel biomarkers – what do they offer? </li></ul><ul><li>Clinical challenges – impact of fluid overload </li></ul><ul><li>Take-home points </li></ul>
  4. 4. Perioperative AKI is NEVER benign!
  5. 5. “ Predictable and avoidable AKI should never occur ” “ Post-operative AKI is avoidable in the elderly and should not occur ”
  6. 6. How do we diagnose & stage AKI? Cruz DN et al. Critical Care 2009; 13 : 211  
  7. 7. The grim reality of real world AKI <ul><li>In 222 non-ICU AKI patients requiring RRT… </li></ul><ul><li>29% of patients died within 30 days 37.6% died within 90 days 51.4% died within one year 34.9% of survivors RRT dependent at 1 year 55% of survivors off RRT by 90d had eGFR < 60 </li></ul>Ng KP, et al. Q J Med 2011, advance access August 22 2011
  8. 8. All grades of AKI matter! Cruz DN, et al. Critical Care 2009; 13 : 211 Ricci Z, et al.   Kidney International 2008; 73: 538-546 Clec ’h C, et al. Crit Care 2011; 15 : R128 Mandelbaum T, et al. Crit Care Med 2011; 39 : Epub ahead of print AKIN
  9. 9. Scoring Perioperative AKI Risk <ul><li>Age > 56 years </li></ul><ul><li>Male gender </li></ul><ul><li>Active CHF </li></ul><ul><li>Ascites </li></ul><ul><li>Hypertension </li></ul><ul><li>Mild to moderate CKD </li></ul><ul><li>Diabetes treated with OHA or insulin </li></ul><ul><li>Emergency surgery </li></ul><ul><li>Intra-peritoneal surgery </li></ul>Kheterpal S, et al. Anesthesiology 2009; 110 : 505-515 Risk factors Hazard ratio 0-2 1 3 3.1 4 8.5 5 15.4 6 46.2
  10. 10. Incidence - emergency surgery N = 61, mean age 75, unpublished audit data
  11. 11. Incidence – elective surgery 1. Thakar CV, et al. Clin J Am Soc Nephrol 2007 ; 2 : 426-430 2. Kheterpal S, et al. Anesthesiology 2007 ; 107 : 892-902 3. Abelha FJ, et al. Crit Care 2009; 13 : R79 4. Kheterpal S, et al. Anesthesiology 2009; 110 : 505-515 5. Molnar AO, et al. J Am Soc Nephrol 2011; 22 : 939-946 Study Population AKI definition AKI incidence Thakar 1 Retrospective 504 patients – gastric bypass > 50% rise in creatinine or need for HD 8.5% Kheterpal 2 Prospective , observational major non-cardiac surgery 15,102 patients creatinine clearance > 80 ml/min Creatinine clearance < 50 ml/min within 7 days of surgery 0.8% Abelha 3 Retrospective , 1,166 patients baseline creatinine < 140 major non-cardiac surgery AKIN stage 1 7.5% Kheterpal 4 Retrospective US national dataset 75,952 general surgery patients creatinine rise of > 167  mol/L from baseline or need for HD 1% (6+ risk factors: 9%) Molnar 5 Retrospective database cohort Major elective surgery including cardiac in 213,347 over 65 ’s Database coding as AKI 1.9%
  12. 12. Early diagnosis – the creatinine issue <ul><li>Variation with muscle mass & age etc. </li></ul><ul><li>Insensitive to rapid changes in renal function </li></ul><ul><li>Insensitive to lesser degrees of dysfunction </li></ul><ul><li>Frequently absent baseline </li></ul><ul><li>Lag time – lost opportunity for therapy </li></ul><ul><li>Altered by fluid shifts and fluid balance 1 </li></ul><ul><ul><li>Positive balance can “hide” AKI </li></ul></ul>1 Liu KD, et al. Crit Care Med 2011; 39 : Epub ahead of print (July 2011)
  13. 13. Biomarkers – the renal crystal ball?
  14. 14. Renal biomarker candidates <ul><li>Kidney injury molecule 1 (KIM-1) </li></ul><ul><li>Cystatin C </li></ul><ul><li>Interleukin 18 (IL-18) </li></ul><ul><li>And others… </li></ul>Neutrophil gelatinase-associated lipocalin (NGAL)
  15. 15. NGAL - what is it? <ul><li>25kDa protein up-regulated in renal injury </li></ul><ul><li>Present in urine and plasma in AKI </li></ul><ul><li>Level rises as early as 2 hours after cell injury </li></ul><ul><li>Falls with successful therapy (animal models) </li></ul><ul><li>Predicts AKI </li></ul><ul><li>Predicts poor outcomes (RRT/death) </li></ul><ul><li>Allows monitoring of therapy </li></ul>Haase M, et al. Curr Opin Crit Care 2010; 16 : 526-532
  16. 16. Biomarker time-course Time (hours) 0 3-6 24 48 NGAL KIM - 1 Cystatin C Creatinine McIlroy DR, Wagener G, Lee HT. Anesthesiology 2010; 112 : 998-1004   Therapeutic window  
  17. 17. NGAL and subclinical AKI <ul><li>NGAL rise only = similar outcomes to NGAL & creatinine rise </li></ul><ul><li>Retrospective pooled design </li></ul>Haase M, et al. J Am Coll Cardiol 2011; 57 : 1752-1761 %
  18. 18. Biomarkers - unresolved issues <ul><li>Bedside vs. laboratory testing </li></ul><ul><li>Lack of “real-world” assay validation </li></ul><ul><li>Timing/frequency of testing uncertain </li></ul><ul><li>Lack of evidence for “what’s best to do next?” </li></ul><ul><li>Impact of testing on outcomes unclear </li></ul>
  19. 19. Challenges in perioperative AKI Needs surgery NOW ! Can we keep up?
  20. 20. AKI Triggers & Perpetuators
  21. 21. AKI hurts other organ systems Grams ME, Rabb H. Kidney International 2011; advance online publication, 3 August 2011
  22. 22. General management <ul><li>Optimise haemodynamics </li></ul><ul><ul><ul><li>Appropriate fluid challenges </li></ul></ul></ul><ul><ul><ul><li>+/- inotrope/pressor (dobutamine/dopamine) </li></ul></ul></ul><ul><li>Stop nephrotoxins & adjust drug doses </li></ul><ul><li>Treat underlying sepsis/obstruction </li></ul><ul><li>Physiological surveillance/management </li></ul><ul><ul><ul><li>Escalate to HDU/ICU ? CRRT </li></ul></ul></ul><ul><li>Nephrology consult ? IHD </li></ul>
  23. 23. Problem areas - fluid overload <ul><li>Fluids do not reverse vasodilatory hypotension </li></ul><ul><li>Associated with poor outcomes </li></ul><ul><li>Causes organ/tissue oedema </li></ul><ul><li>Causes venous congestion </li></ul><ul><li>Worsens tissue perfusion </li></ul><ul><li>Intra–abdominal hypertension </li></ul>
  24. 24. Fluid overload & adverse outcome 1 Grams ME, et al. Clin J Am Soc Nephrol 2011; 6 : 966-973 2 Boyd JH, et al. Crit Care Med 2011; 39 : 259-265 3 Sutherland SM, et al. Am J Kid Dis 2010; 55 : 316-325 4 Bouchard J, et al . Kidney Int 2009; 76 : 422-427 5 Payen D, et al. Crit Care 2008; 12 : R74 6 Wiedemann HP, et al. N Engl J Med 2006; 354 : 2564-2575 7 de-Madaria E, et al. Am J Gastroenterol 2011. Epub 30/08/2011 Population N Design Results ARDS + AKI 1 306 Retrospective analysis of RCT Strong association + ve balance and mortality Septic shock 2 778 Retrospective analysis of RCT + ve balance correlated with increased mortality AKI 3 297 Prospective cohort More + ve balance associated with mortality AKI 4 618 Prospective cohort More + ve balance associated with mortality ICU 5 1,120 Prospective cohort More + ve balance associated with mortality ARDS 6 1,000 RCT Conservative balance = shorter ventilation time Pancreatitis 7 247 Prospective cohort More + ve balance associated with increased organ failures
  25. 25. Fluid overload causes tissue oedema Prowle JR, et al. Nat Rev Nephrol 2010; 6 : 107-115 Cerebral Altered mental status Myocardial Arrhythmia, diastolic/systolic dysfunction Pulmonary Impaired gas exchange, increased work Hepatic Cholestasis Renal Decreased RBF & GFR, venous congestion Gut Ileus, anastomotic breakdown Tissue Poor healing, pressure ulcers, infections
  26. 26. Fluid overload worsens tissue perfusion <ul><li>Shedding of endothelial glycocalyx </li></ul><ul><ul><ul><li>Triggered by hypervolaemia (ANP) & inflammation 1 </li></ul></ul></ul><ul><ul><ul><li>Loss of vascular integrity => leak </li></ul></ul></ul><ul><ul><ul><li>Leukocyte/platelet adhesion => microthrombi </li></ul></ul></ul>1 Bruegger D, et al. Basic Res Cardiol 2011; 19 th July Online First
  27. 27. Microvascular responses to fluid <ul><li>Differs from the macro-haemodynamic response </li></ul><ul><li>Improvement in CO and BP do not guarantee improvement in microvascular perfusion </li></ul><ul><li>Positive microvascular response to fluid bolus diminishes significantly over time </li></ul>Pottecher J, et al. Intensive Care Med 2010; 36 : 1874 Ospina-Tascon G, et al. Intensive Care Med 2010; 36 : 949-955 Harrois A, et al. Curr Opin Crit Care 2011; 17 : 303-307
  28. 28. Intra-abdominal hypertension <ul><li>Normal I ntra- A bdominal P ressure < 7 mmHg </li></ul><ul><li>Normal A bdominal P erfusion P ressure > 75 mmHg </li></ul><ul><li>APP = Mean arterial pressure (MAP) – IAP </li></ul><ul><li>Renal filtration gradient = MAP – 2*IAP </li></ul><ul><li>Decreased RBF, increased venous pressures </li></ul><ul><li>Impaired gut blood flow & gut translocation </li></ul><ul><li>IAP > 20 + organ failure = compartment syndrome </li></ul>
  29. 29. So what should we do? <ul><li>THINK before fluids and MONITOR after </li></ul><ul><li>Early fluid resuscitation is appropriate </li></ul><ul><li>Usually leads to early positive balance </li></ul><ul><li>Make the switch </li></ul><ul><ul><li>Even balance by 48 hours, negative beyond this </li></ul></ul><ul><ul><li>Diuretics or UF </li></ul></ul><ul><ul><li>Earlier move to inotropes/pressors </li></ul></ul><ul><li>Make it part of daily practice </li></ul>
  30. 30. Take-home points <ul><li>Any degree of AKI = worse outcome </li></ul><ul><li>Risk recognition and tailored journey </li></ul><ul><ul><li>More haemodynamic optimisation? </li></ul></ul><ul><ul><li>Earlier recourse to HDU/ICU? </li></ul></ul><ul><li>Biomarkers = earlier intervention </li></ul><ul><li>Fluid timing and balance are critical </li></ul><ul><li>Renal rescue bundles? </li></ul>
  31. 31. <ul><ul><li>“ Poison is in everything, </li></ul></ul><ul><ul><li>and no thing is without poison. </li></ul></ul><ul><ul><li>The dosage makes it either </li></ul></ul><ul><ul><li>a poison or a remedy ” </li></ul></ul><ul><ul><li>Philippus Aureolus Theophrastus Bombastus von Hohenheim </li></ul></ul><ul><ul><li>“ Paracelsus ” (1493-1541) </li></ul></ul>
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