ACUTE RENAL FAILURE

John Feehally
ACUTE RENAL FAILURE

ACUTE KIDNEY INJURY

ACUTE KIDNEY INJURY

Outcomes

Causes

Diagnosis

Prevention & Management

MORTALITY IN ACUTE KIDNEY INJURY
AGE & OUTCOME IN ACUTE KIDNEY INJURY
 PREDICTING OUTCOME IN
ACUTE KIDNEY INJURY IN ITU

Overall mortality remains 75%

Scoring systems [e.g. APACHE-II, POSSUM]

Age

Pre-existing vascular disease

Disease – specific data are needed

Effect of changes in serum creatinine
on mortality after cardiac surgery
FALLING MORTALITY IN ACUTE RENAL FAILURE
Nationwide In-Patient Sample – USA –
1988-2002
• Increasing incidence of reported ARF
• Increasing co-morbidity

Waikar SS et al. JASN 2006; 17: 1143

 ACUTE KIDNEY INJURY

HOW COMMON IS IT ?

Problem of definitions

ESTIMATES

ADULTS ~200 – 500 pmp per year

CHILDREN ~7.5 pmp per year

RECOVERY FROM ACUTE KIDNEY INJURY

ATN typically recovers

in 3 days to 6 weeks
RISK FACTORS FOR ACUTE KIDNEY INJURY

Emergency & planned admissions

Older

Comorbidity
Vascular disease
Pre-existing CKD

Medication

Younger
RISK FACTORS FOR ACUTE KIDNEY INJURY

Emergency & planned admissions

Older

Comorbidity
Vascular disease
Pre-existing CKD
ACE inhibitors/ ARB

Medication NSAIDs

Aminoglycosides
Younger
 PREVENTION OF ACUTE KIDNEY INJURY

Role of the nephrologist

Outside hospital
Risk awareness
Medical wards

Surgical wards

Education Critical care

ACUTE KIDNEY INJURY

Outcomes

Causes

Diagnosis

Management
 ACUTE KIDNEY INJURY

INADEQUATE
RENAL PERFUSION

ACUTE TUBULAR NECROSIS

 ACUTE KIDNEY INJURY

TRUE
HYPOVOLAEMIA
INADEQUATE
RENAL PERFUSION

REDUCED ‘EFFECTIVE’
ECF VOLUME

ACUTE TUBULAR NECROSIS

 ACUTE KIDNEY INJURY

TRUE
HYPOVOLAEMIA
INADEQUATE
RENAL PERFUSION

REDUCED ‘EFFECTIVE’
ECF VOLUME

Cardiac failure

Systemic vasodilatation
Sepsis
ACUTE TUBULAR NECROSIS Cirrhosis
Anaphylaxis

Impaired glomerular autoregulation

 ACUTE KIDNEY INJURY

TRUE
HYPOVOLAEMIA
INADEQUATE
RENAL PERFUSION

REDUCED ‘EFFECTIVE’
ECF VOLUME
Preglomerular (afferent) constriction
Sepsis Cardiac failure
Hypercalcaemia
Hepatorenal syndrome Systemic vasodilatation
Drugs Sepsis
NSAIDs CNIs Amphotericin Adrenaline Cirrhosis
Anaphylaxis
Postglomerular (efferent) dilatation
ACE inhibitors ARBs Impaired glomerular autoregulation
 ACUTE KIDNEY INJURY

TRUE
HYPOVOLAEMIA
INADEQUATE
RENAL PERFUSION

REDUCED ‘EFFECTIVE’
ECF VOLUME

ACUTE TUBULAR NECROSIS

 ACUTE KIDNEY INJURY

SEPSIS
INADEQUATE
RENAL PERFUSION +

ACUTE TUBULAR NECROSIS

 ACUTE KIDNEY INJURY

SEPSIS
INADEQUATE
RENAL PERFUSION +
NEPHROTOXINS

ACUTE TUBULAR NECROSIS

 +
Intrarenal
vasoconstriction
 ATN

Flattened tubular epithelium Luminal debris

RECOVERY
ACUTE TUBULAR NECROSIS

ATN is reversible

ATN describes the histology

+
[which is variable]

It is not an ideal term – but widely used

ACUTE TUBULAR NECROSIS

 ACUTE RENAL FAILURE

‘ACUTE RENAL SUCCESS’ ?

Tubular dysfunction

Isosmolar urine

Thurau 1976
 ACUTE RENAL FAILURE

‘ACUTE RENAL SUCCESS’ ?

Tubular dysfunction

Isosmolar urine

Vasoconstriction Tubuloglomerular feedback

RPF GFR
Thurau 1976
 ACUTE KIDNEY INJURY

SEPSIS
INADEQUATE
RENAL PERFUSION +
NEPHROTOXINS
 ACUTE KIDNEY INJURY

SEPSIS
INADEQUATE
RENAL PERFUSION +
NEPHROTOXINS

ENDOGENOUS

Myoglobin

Bilirubin

Urate
 MYOGLOBINURIA

TRAUMATIC NON-TRAUMATIC

Crush Injury Influenza

Extreme exertion Myopathies

Exercise McArdles
Fits alcoholic
Tetanus Polymyositis

Ischaemia Prolonged coma

Alcohol
Burns Narcotics
 ACUTE KIDNEY INJURY

SEPSIS
INADEQUATE
RENAL PERFUSION +
NEPHROTOXINS

ENDOGENOUS

Myoglobin

Bilirubin

Urate
 ACUTE KIDNEY INJURY

SEPSIS
INADEQUATE
RENAL PERFUSION +
NEPHROTOXINS
EXOGENOUS

Medicines ENDOGENOUS

Contrast Myoglobin

Poisons Bilirubin

Endotoxin Urate
 ACUTE KIDNEY INJURY

SEPSIS
INADEQUATE
RENAL PERFUSION +
NEPHROTOXINS

Aminoglycosides
EXOGENOUS

NSAIDs Medicines ENDOGENOUS

ACEi & ARB Contrast Myoglobin

Poisons Bilirubin

Endotoxin Urate
 ACUTE KIDNEY INJURY

Not all AKI is ATN

PRE-RENAL ? RENAL ? POST-RENAL ?

 ACUTE KIDNEY INJURY

PRE-RENAL ? RENAL ? POST-RENAL ?

 CAUSES OF ACUTE KIDNEY INJURY

RENAL

ATN 55%
PRE-RENAL 30% POST-RENAL 10%
Other parenchymal
renal disease 5%
GN
Acute interstitial nephritis
Thrombotic microangiopathy
Myeloma kidney
 CAUSES OF ACUTE KIDNEY INJURY

RENAL

ATN 55%
PRE-RENAL 30% POST-RENAL 10%
Other parenchymal
renal disease 5%
GN
Acute interstitial nephritis
Thrombotic microangiopathy
Myeloma kidney
ACUTE KIDNEY INJURY

Outcomes

Causes

Diagnosis

Management
Clinical Assessment of Acute Kidney Injury
History nb drug history
evidence of CKD

Physical examination
nb fluid and volume status

Chart Review drug charts

BP + fluid charts
anaesthetic records

Urine examination stick test

microscopy
biochemistry
Look at the ‘numbers’

BUT

Look at the patient first

 ACUTE KIDNEY INJURY

Pre-renal Are the kidneys underperfused ?

Are nephrotoxins implicated ?

Renal Is ATN established ?

Is there a parenchymal renal disease

other than ATN ?

Post-renal Is there renal tract obstruction ?

ATN does not cause ABSOLUTE ANURIA

Consider ……

OBSTRUCTION

VASCULAR
OCCLUSION
 ATN does not cause ABSOLUTE ANURIA

Check bladder catheter

Most obstructed patients are polyuric

OBSTRUCTION
Ultrasound shows PC dilatation in 95%
misses ureteric stones
so combine with KUB or CT

Clinical pelvic examination is mandatory

Relieve obstruction rapidly

 ATN does not cause ABSOLUTE ANURIA

Bilateral arterial occlusion ANURIA

Incomplete occlusion + circulatory failure ANURIA

VASCULAR
OCCLUSION
Widespread atheromatous vascular disease

Anuria may not = infarcted kidney

 URINE EXAMINATION IN AKI
Proteinuria Haematuria Microscopy

Pre-renal failure - - Normal

Vascular occlusion - - Normal

Acute GN +++ +++ RBC casts

dysmorphic RBCs

Acute interstitial ++ + Pyuria

nephritis WBC casts

HUS/TTP - + Normal

ATN - - Granular casts

THROMBOCYTOPENIA & ACUTE KIDNEY INJURY

Thrombocytopenia is not a feature of AKI per se

Sepsis ATN

Lupus

Myeloma

Thrombotic microangiopathy
 ACUTE KIDNEY INJURY

Pre-renal Are the kidneys underperfused ?

Renal Is ATN established ?

 ACUTE KIDNEY INJURY

Pre-renal Are the kidneys underperfused ?

Fluid challenge ?
or
Fluid restrict ?

Renal Is ATN established ?

 SERUM UREA:CREATININE RATIO
IN ACUTE KIDNEY INJURY

HIGH LOW

Pre-renal failure Low urea production

Malnutrition
High urea production Severe .liver disease
catabolic
g-i bleed High creatinine release
corticosteroids rhabdomyolysis
 URINE CHEMISTRY IN ACUTE KIDNEY INJURY

Pre-renal ATN

Urine: plasma osmolality > 1.5 < 1.1

Urine: plasma urea >8 <3

Urine sodium - mmol/L < 10 > 40

Fractional excretion sodium < 1% > 2%

FENa+
 URINE CHEMISTRY IN ACUTE KIDNEY INJURY

Pre-renal ATN

Urine: plasma osmolality > 1.5 < 1.1

Urine: plasma urea >8 <3
Urine sodium - mmol/L < 10 > 40
Fractional excretion sodium < 1% > 2%

Helpful if parameters are ‘pre-renal’

Parameters of ‘ATN’ cannot be interpreted if –

a) already had diuretic
b) elderly
c) pre-existing renal disease
 BIOMARKERS PREDICTING AKI
The most promising candidates
to be in a ‘panel’ for AKI prediction are
Abbreviation Name Indicates
KIM-1 Kidney Injury Molecule -1 Proximal ischaemic
injury

NGAL Neutrophil gelatinase- Ischaemic/nephrotoxic

associated lipocalin injury

IL-18 Interleukin-18 Ischaemicinjury

CYC Cystatin C Reduced GFR

BIOMARKERS PREDICTING AKI

CARDIAC SURGERY

In first 6 hours after surgery ….

Rise of urine NGAL & urine Cystatin C

predicts AKI

Kayner J et al. 2008 Kidney Int epub 23 July

 BIOMARKERS PREDICTING AKI

EMERGENCY ROOM

Single measurement of urine NGAL predicted AKI

95% sensitivity - 99% specificity

Also predicted need for

Nephrology referral
Dialysis
Trnasfer to ICU

Nickolas TL et al. 2008 Ann Intern Med; 148: 810

BIOMARKERS PREDICTING AKI

Promising, but need ….

Rapid point of care testing

Prospective testing of multiple parameters

Interventions which make a difference

ACUTE KIDNEY INJURY

Outcomes

Causes

Diagnosis

Prevention & Management

MANAGEMENT OF OLIGURIA

Correct volume
Clinical assessment, CVP

Correct BP - inotropes

What is the correct BP for this patient ?

MANAGEMENT OF OLIGURIA

Correct volume
Clinical assessment, CVP

Correct BP - inotropes
‘RENAL DOSE’ DOPAMINE

2 µg/kg/min

NORMAL KIDNEYS

Vasodilatation & diuresis

… but what does it do

in sick oliguric patients ?
 DOPAMINE DOES NOT PREVENT AKI

µg/kg/min throughout ITU stay

RCT - dopamine 2µ

Lancet 2000;356:2139
 DOPAMINE DOES NOT PREVENT AKI

µg/kg/min throughout ITU stay

RCT - dopamine 2µ

...and no effect on
development
of AKI

Lancet 2000;356:2139
MANAGEMENT OF OLIGURIA

Correct volume
Clinical assessment, CVP

Correct BP - inotropes

dopamine not indicated

MANAGEMENT OF OLIGURIA

Correct volume
Clinical assessment, CVP

Correct BP - inotropes

dopamine not indicated

DIURETIC

Mannitol 20% 100ml [if jaundiced]

Furosemide 250-500mg [not with aminoglycosides]

 LOOP DIURETICS IN AKI

n = 92

Pre-renal corrected

Post-renal excluded

All received mannitol for 3 days and low dose dopamine

DOUBLE BLIND RCT OF LOOP DIURETIC

Furosemide or Torasemide

Shilliday I et al. NDT 1997; 12: 2592

 LOOP DIURETICS IN AKI

n = 92 - double blind RCT

Significant increase in urine volume over first 24 hrs

but…….

No effect on

Mortality

Need for dialysis

Renal recovery

Shilliday 1997 NDT;12:2592

PREVENTION OF ACUTE KIDNEY INJURY

Volume loading

Mannitol [if jaundiced]

There is no evidence that

‘renal dose’ dopamine or furosemide

prevent AKI in high risk patients

MANAGEMENT OF AKI

Fluid balance

Potassium

Acidosis

Uraemia
MANAGEMENT OF AKI

Fluid balance

Potassium

Acidosis

Uraemia
FUROSEMIDE IN ACUTE KIDNEY INJURY

OLIGURIA – incipient AKI

No evidence furosemide prevents AKI

ESTABLISHED AKI

No evidence furosemide improves outcome or speeds recovery

It may produce a small rise in urine volume

 NUTRITION IN AKI

AKI is a catabolic illness

Starvation worsens catabolism

Low protein diet aggravates negative nitrogen balance

Feed early and maximally

If this fluid overload : DIALYSE

MANAGEMENT OF AKI

Fluid balance

Potassium

Acidosis

Uraemia
 HYPERKALAEMIA

ECG changes may not correlate with serum K level

Hyperkalaemia aggravated by

acidosis

sepsis

catabolism

dead tissue
TREATMENT OF HYPERKALAEMIA

Protect heart
no change in serum K

Calcium

Shift K into cells

Insulin/glucose
Bicarbonate
Salbutamol

Remove K from body

Calcium resonium
Dialysis
MANAGEMENT OF AKI

Fluid balance

Potassium

Acidosis

Uraemia
 METABOLIC ACIDOSIS IN AKI

ANION GAP > 20

Na – Cl – HCO3

LACTIC ACIDOSIS
URAEMIA
Circulatory failure
50-100 mmol/day
Liver failure
Poisoning
Diabetic ketoacidosis
……
MANAGEMENT OF METABOLIC ACIDOSIS IN AKI

It may be severe and resistant

… especially if there is dead tissue

Think of : compartments ?
ischaemic bowel ?
 BICARBONATE DEFICIT

Deficit [mmol] =

0.4 x lean body weight

x [desired – measured] serum bicarbonate

TREATMENT OF METABOLIC ACIDOSIS IN AKI

iv NaHCO3

Haemodialysis

Haemofiltration
TREATMENT OF METABOLIC ACIDOSIS IN AKI

When to treat ?

pH < 7.2 ITU pH < 7.3

Why treat ?

Acidosis causes inotrope resistance ?

How to treat ?

Sodium bicarbonate

Risks unproven

Prefer isotonic 1.4%

Problem of volume overload

TREATMENT OF METABOLIC ACIDOSIS

Possible risks of sodium bicarbonate therapy

Volume overload & hypertoncity

Intracellular acidosis

Respiratory acidosis

CNS acidosis

In practice these are less than expected…

.. and can mostly be avoided

MANAGEMENT OF ARF

Fluid balance

Potassium

Acidosis

Uraemia
 URAEMIC BLEEDING DIATHESIS

Platelet aggregation and adhesion

von Willebrand factor is the main platelet ‘glue’

 URAEMIC BLEEDING DIATHESIS

Defective platelet adhesion and aggregation

Inhibited by uraemic factors

von Willebrand factor is the main platelet ‘glue’

URAEMIC BLEEDING DIATHESIS

Treatment

Remove uraemic factors

DIALYSIS

Provide additional vWF

CRYOPRECIPITATE

DDAVP
RENAL REPLACEMENT THERAPY IN AKI

Peritoneal dialysis
______

Haemodialysis

Haemofiltration
CONTINUOUS RENAL REPLACEMENT THERAPY
FOR AKI

Convenience ?

Technical simplicity ?

Cardiovascular tolerability ?

Biocompatibility ?

Clearance of toxins, mediators ?

RENAL REPLACEMENT THERAPY FOR AKI

Haemodialysis or Haemofiltration ?

Intermittent or Continuous ?

Dose ?
RENAL REPLACEMENT THERAPY FOR AKI

Haemodialysis or Haemofiltration ?

Intermittent or Continuous ?

Dose ?

OUTCOME MEASURES

Survival

Duration of oliguria

Recovery GFR
 RENAL REPLACEMENT THERAPY IN ITU
Continuous or Intermittent ?

RCT n = 166

Intermittent Haemodialysis vs. Continuous Haemodiafiltration

There was no difference in –

Recovery of renal function

ITU stay

In-hospital mortality

Mehta R et al. KI 2001; 60: 1154

RENAL REPLACEMENT THERAPY IN
ACUTE KIDNEY INJURY

What is the most effective dose ?

 HIGHER DOSE RRT BENEFICIAL
IN ACUTE KIDNEY INJURY

RCT n = 425

Post-dilutional CVVH

20 ml/hr/kg vs. 35 ml/hr/kg vs. 45ml/hr/kg

Survival significantly reduced [41% vs. 57%]

if only receive 20 ml/hr/kg

Ronco C et al. Lancet 2001; 356: 26

HIGHER DOSE RRT BENEFICIAL
IN ACUTE KIDNEY INJURY

RCT - Intermittent HD

DAILY better than THREE TIMES WEEKLY

…. but three times weekly group probably underdialysed

Mean pre-dialysis urea 37 mmol/l

Schiffl H et al. NEJM 2002; 346: 305

 HIGHER DOSE RRT NOT BENEFICIAL
IN ACUTE KIDNEY INJURY

LESS INTENSIVE MORE INTENSIVE

3 / week Mean 5.4 / week

Intermittent HD Intermittent HD
or or
SLED SLED

OR OR

CVVH CVVH
Mean 21.5 ml/kg/hr Mean 36.2 ml/kg/hr

Palevsky P et al. NEJM 2008; 359: 7

 HIGHER DOSE RRT NOT BENEFICIAL
IN ACUTE KIDNEY INJURY

LESS INTENSIVE MORE INTENSIVE

3 / week Mean 5.4 / week

Intermittent HD Intermittent HD
or or
SLED Patients changed modalities SLED
as clinically indicated
OR OR

CVVH CVVH
Mean 21.5 ml/kg/hr Mean 36.2 ml/kg/hr

Palevsky P et al. NEJM 2008; 359: 7

 HIGHER DOSE RRT NOT BENEFICIAL
IN ACUTE KIDNEY INJURY

LESS INTENSIVE
4340 screened MORE INTENSIVE

3 / week 1124 randomised Mean 5.4 / week

Intermittent HD Intermittent HD
or or
SLED Patients changed modalities SLED
as clinically indicated
OR OR

CVVHDF CVVHDF
Mean 21.5 ml/kg/hr Mean 36.2 ml/kg/hr

Palevsky P et al. NEJM 2008; 359: 7

HIGHER DOSE RRT NOT BENEFICIAL
IN ACUTE KIDNEY INJURY

Palevsky P et al. NEJM 2008; 359: 7

 CHOICE OF RRT MODALITY IN AKI

On available evidence….

Use convenient technique

Providing cardiovascular stability

Use conventional clinical markers of adequacy