Perioperative Acute Kidney Injury

Biomarkers, Physicians, and the Surgical Abdomen

Dr. Andrew FergusonDepartment of Anaesthetics & Intensive Care Medicine

Craigavon Area Hospital

Disclosures

• No conflicts of interest to declare

Outline

• Why AKI matters to us

• Diagnostic and staging criteria for AKI

• AKI risk factors in perioperative patients

• Novel biomarkers – what do they offer?

• Clinical challenges – impact of fluid overload

• Take-home points

Perioperative AKI is NEVER benign!

“Predictable and avoidable AKIshould never occur”

“Post-operative AKI is avoidable in the elderly and should not occur”

How do we diagnose & stage AKI?

Cruz DN et al. Critical Care 2009; 13: 211

Ng KP, et al. Q J Med 2011, advance access August 22 2011

The grim reality of real world AKI

In 222 non-ICU AKI patients requiring RRT…

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

All grades of AKI matter!

Cruz DN, et al. Critical Care 2009; 13: 211Ricci Z, et al. Kidney International 2008; 73: 538-546Clec’h C, et al. Crit Care 2011; 15: R128Mandelbaum T, et al. Crit Care Med 2011; 39: Epub ahead of print

AKIN

Scoring Perioperative AKI Risk• Age > 56 years• Male gender• Active CHF• Ascites• Hypertension• Mild to moderate CKD• Diabetes treated with OHA or insulin• Emergency surgery• Intra-peritoneal surgery

Risk factors Hazard ratio0-2 13 3.14 8.55 15.46 46.2

Kheterpal S, et al. Anesthesiology 2009; 110: 505-515

Incidence - emergency surgery

N = 61, mean age 75, unpublished audit data

Incidence – elective surgeryStudy Population AKI definition AKI incidence

Thakar 1 Retrospective504 patients – gastric bypass

> 50% rise in creatinine or need for HD 8.5%

Kheterpal 2Prospective, observational major non-cardiac surgery 15,102 patients creatinine clearance > 80 ml/min

Creatinine clearance < 50 ml/min within 7 days of

surgery0.8%

Abelha 3Retrospective, 1,166 patientsbaseline 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 HD1%

(6+ risk factors: 9%)

Molnar 5Retrospective database cohortMajor elective surgery including cardiac in 213,347 over 65’s

Database coding as AKI 1.9%

1. Thakar CV, et al. Clin J Am Soc Nephrol 2007; 2: 426-430 2. Kheterpal S, et al. Anesthesiology 2007; 107: 892-9023. Abelha FJ, et al. Crit Care 2009; 13: R79 4. Kheterpal S, et al. Anesthesiology 2009; 110: 505-5155. Molnar AO, et al. J Am Soc Nephrol 2011; 22: 939-946

Early diagnosis – the creatinine issue

• Variation with muscle mass & age etc.• Insensitive to rapid changes in renal function• Insensitive to lesser degrees of dysfunction• Frequently absent baseline

Lag time – lost opportunity for therapy Altered by fluid shifts and fluid balance1

–Positive balance can “hide” AKI

1 Liu KD, et al. Crit Care Med 2011; 39: Epub ahead of print (July 2011)

Biomarkers – the renal crystal ball?

Renal biomarker candidates

• Kidney injury molecule 1 (KIM-1)• Cystatin C• Interleukin 18 (IL-18)• And others…

Neutrophil gelatinase-associated lipocalin (NGAL)

NGAL - what is it?• 25kDa protein up-regulated in renal injury

• Present in urine and plasma in AKI

• Level rises as early as 2 hours after cell injury

• Falls with successful therapy (animal models)

Predicts AKI

Predicts poor outcomes (RRT/death)Allows monitoring of therapy

Haase M, et al. Curr Opin Crit Care 2010; 16: 526-532

Time (hours)0 3-6 24 48

NGAL

KIM - 1

Cystatin C

Creatinine

McIlroy DR, Wagener G, Lee HT. Anesthesiology 2010; 112: 998-1004

Biomarker time-course Therapeutic window

02468

101214161820

NGAL -/Creat -

NGAL +/Creat -

NGAL-/Creat +

NGAL +/Creat +

RRTHosp deathComposite

NGAL and subclinical AKI

• NGAL rise only = similar outcomes to NGAL & creatinine rise• Retrospective pooled design

Haase M, et al. J Am Coll Cardiol 2011; 57: 1752-1761

%

Biomarkers - unresolved issues

• Bedside vs. laboratory testing

• Lack of “real-world” assay validation

• Timing/frequency of testing uncertain

• Lack of evidence for “what’s best to do next?”

• Impact of testing on outcomes unclear

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• Optimise haemodynamics

• Appropriate fluid challenges

• +/- inotrope/pressor (dobutamine/dopamine)

• Stop nephrotoxins & adjust drug doses• Treat underlying sepsis/obstruction• Physiological surveillance/management

• Escalate to HDU/ICU ? CRRT

• Nephrology consult ? IHD

Problem areas - fluid overload• Fluids do not reverse vasodilatory hypotension

• Associated with poor outcomes

• Causes organ/tissue oedema

• Causes venous congestion

• Worsens tissue perfusion

• Intra–abdominal hypertension

Fluid overload & adverse outcomePopulation 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

1 Grams ME, et al. Clin J Am Soc Nephrol 2011; 6: 966-9732 Boyd JH, et al. Crit Care Med 2011; 39: 259-2653 Sutherland SM, et al. Am J Kid Dis 2010; 55: 316-325

4 Bouchard J, et al. Kidney Int 2009; 76: 422-4275 Payen D, et al. Crit Care 2008; 12: R746 Wiedemann HP, et al. N Engl J Med 2006; 354: 2564-25757 de-Madaria E, et al. Am J Gastroenterol 2011. Epub 30/08/2011

Fluid overload causes tissue oedema

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

Prowle JR, et al. Nat Rev Nephrol 2010; 6: 107-115

Fluid overload worsens tissue perfusion

• Shedding of endothelial glycocalyx• Triggered by hypervolaemia (ANP) & inflammation 1

• Loss of vascular integrity => leak• Leukocyte/platelet adhesion => microthrombi

1 Bruegger D, et al. Basic Res Cardiol 2011; 19th July Online First

Microvascular responses to fluid

• Differs from the macro-haemodynamic response

• Improvement in CO and BP do not guarantee

improvement in microvascular perfusion

• Positive microvascular response to fluid bolus

diminishes significantly over time

Pottecher J, et al. Intensive Care Med 2010; 36: 1874Ospina-Tascon G, et al. Intensive Care Med 2010; 36: 949-955Harrois A, et al. Curr Opin Crit Care 2011; 17: 303-307

Intra-abdominal hypertension• Normal Intra-Abdominal Pressure < 7 mmHg• Normal Abdominal Perfusion Pressure > 75 mmHg

APP = Mean arterial pressure (MAP) – IAPRenal filtration gradient = MAP – 2*IAP

• Decreased RBF, increased venous pressures• Impaired gut blood flow & gut translocation• IAP > 20 + organ failure = compartment syndrome

So what should we do?• THINK before fluids and MONITOR after

• Early fluid resuscitation is appropriate

• Usually leads to early positive balance

• Make the switch

– Even balance by 48 hours, negative beyond this

– Diuretics or UF

– Earlier move to inotropes/pressors

• Make it part of daily practice

Take-home points

• Any degree of AKI = worse outcome

• Risk recognition and tailored journey

– More haemodynamic optimisation?

– Earlier recourse to HDU/ICU?

• Biomarkers = earlier intervention

• Fluid timing and balance are critical

• Renal rescue bundles?

“Poison is in everything, and no thing is without poison.

The dosage makes it either a poison or a remedy”

Philippus Aureolus Theophrastus Bombastus von Hohenheim “Paracelsus” (1493-1541)