AKI
Diagnosis
Pathogenesis
Therapy
John R. Prowle MSc MB BChir MRCP FFICM
Consultant Intensivist Royal London Hospital
Summary
• Early diagnosis of AKI is difficult
• Pathogenesis is multifactorial
• Maintain CO, BP and remove
nephrotoxins
• Do no harm
• Supportive RRT if indicated
• CRRT in the ICU
Functions of the Kidney
•
•
Salt, Water and Acid-base balance
•
•
•
•
•
•
Excretion of Nitrogenous End Products
•
•
•
•
•
•
Water
Sodium
Potassium
Bicarbonate
Magnesium
Phosphate
Urea
Creatinine
Uric acid
Amines
Guanidine derivatives
Endocrine / Metabolic
•
•
•
Renin
Erythropoetin
1,25-DHCC
Acute & Chronic Consequences of Renal Dysfunction
•
Salt, Water and Acid-base balance
•
•
•
•
•
•
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Oedema, CHF, Hypertension
Hyperkalaemia
Acidosis, Osteodystrophy
Hypermagnesemia
Hyperphosphataemia, Osteodystrophy
Excretion of Nitrogenous End Products
•
•
Fluid retention, Hyponatraemia
Anorexia, Nausea, Puritis, Pericarditis,
Polyneuropathy, Encephalopathy,
Platelet dysfunction.
Endocrine / Metabolic
•
•
•
Hypertension
Anaemia
Osteomalcia, Osteodystrophy
Case #1
• 25 yr old male presents with a four hour history of
headache confusion and non-blanching skin rash.
• He was well the previous day
• BP 95/40 HR 130 T 38.1 RR 35
• Creatinine 150
• What’s was his likely baseline creatinine?
• Does he have AKI? - How Severe?
• He admitted to ICU, after 18hr his Creat is 300 and he’s
passed 200ml of Urine. He’s Intubated, on 0.8mcg/kg/
min Noradrenaline and has received 5L of Fluid.
• How severe is his AKI now?
• Has his GFR fallen since admission?
• Will he need RRT?
Case #2
• 80yr old male falls and fractures his hip
• His ACE-In was continued despite BP 105/45 and
a stat dose of Voltarol for pain on the ward.
• He waits 48hr NBM for his hemiarthroplasty
• He’s severely hypotensive intra-operatively with
cement insertion
• He admitted to HDU post-operatively for BP
support
• He has a cough with green sputum and R basal
creps when he arrives in HDU
Case #2 cont
• Admission and day 1 Creat was 80
• What was his baseline GFR?
• Does he have CKD?
• Creat on HDU admission was 135
• What’s his GFR??
• Can we classify the severity of his AKI?
• Will he need RRT?
• His BP is 85/35 despite 2L of iv fluid, his UO is 5ml/hr
• How should we treat his hypotension?
AKI: Diagnosis
• Sudden and sustained decrease in
Glomerular Filtration Rate leading
to accumulation of Urea and other
toxins in the bloodstream.
• A loose and not terribly useful
definition.
GFR & Creatinine
• Steady State
IN = OUT
• Clearance x [Creatinine] = Generation Rate
• GFR α 1/Creatinine
• Steady State
• Basis of eGFR
• eGFR is only valid in Steady State
• When in new steady state a doubling of Creatinine
implies a halving of GFR.
Steady State: In = Out
G =K.Cr
G
K=
Cr
Double Creatinine = Half GFR
Creatinine Production
Creatinine
GFR and Plasma Creatinine in Steady State
Position of Curve is Shifted to Left by Lower Muscle Mass
GFR & Creatinine
• Creatinine generation rate (G) determines
relationship between GFR and Creatinine in steady
state and rate of rise in creatinine in AKI
• Age, Sex, Race, Diet, Muscle Mass & Liver function
determine G.
• G is acute affected by acute illness.
• Changes in volume of distribution (V) may also
acutely alter [Creatinine].
Cases - Baseline
• A 25 yr old male might typically have a
GFR of 120ml/min and a Creatinine of
80µmol/L.
• A 80yr old man with a Creatinine of 80
would have a GFR of around 65ml/min.
• Timing and generation rate deterimine
significant of acute creatinine changes.
100
50
0
Creatinine
150
200
25 yr old man whose GFR acutely falls from 120 to 60 ml/min
0
10
20
30
time (hrs)
40
50
100
50
0
Creatinine
150
200
80 yr old man whose GFR acutely falls from 65 to 32.5 ml/min
0
10
20
30
time (hrs)
40
50
0
10
20
30
time (hrs)
40
50
0
50
100
Creatinine
150
200
300
200
100
0
Creatinine
400
500
600
20 yr old man whose GFR acutely falls from 120 to 10 ml/min
0
10
20
30
time (hrs)
40
50
300
200
100
0
Creatinine
400
500
600
80 yr old man whose GFR acutely falls from 65 to 10 ml/min
0
10
20
30
time (hrs)
40
50
300
200
100
0
Creatinine
400
500
600
80 yr old man whose GFR acutely falls from 65 to 10 ml/min with a 1/3 fall in G
0
10
20
30
time (hrs)
40
50
Oliguria
“Pre-Renal Failure”
“Acute Renal Success”
Appropriate renal salt and water
conservation “Acute Renal Success”.
Reversible reduction in Renal Blood Flow
and decreased GFR “Pre-Renal Failure”.
Sustained reduction in GFR in Acute
Kidney Injury.
AKI
Oliguria
AKI?
ADH, Sympathetic and ReninAngiotensin responses to Pain and
Injury may trigger salt and water
conser vation even when blood
pressure, cardiac output and volume
status are adequate.
AKI
Oliguria?
Loss of concentrating capacity in acute
and chronic kidney disease or with
diuretic therapy.
If maximal concentrating capacity is low
oliguria will only occur when GFR has
fallen to a very low level.
Summary....
• Elevated Creatinine and Sustained
Oliguria are late consequences of AKI.
• This has implications for treatment.
AKI: Epidemiology
Figure 2 Percentage distribution of causes of acute renal failure in (A) non-ICU
and (B) ICU settings
Modified with permission from Liano F et al. (1998) The spectrum of acute renal failure in the intensive care unit
compared with that seen in other settings. The Madrid Acute Renal Failure Study Group.
Kidney Int Suppl 66: S16–S24. © (1998) Nature Publishing Group.
Lameire N et al. (2006) The changing epidemiology of acute renal failure
Nat Clin Pract Neprol 2: 364–377 doi:10.1038/ncpneph0218
AKI: Pathogenesis
• AKI rapidly reversible with
restoration of haemodynamic insult.
• “Pre-renal”
• Sustained AKI persisting for days to
weeks after removal of acute insult.
• “ATN” / Tubular Injury
But Don’t Forget Nephrologists and
Urologists are Occasionally Useful
• Active urinary sediment - ?GN
• Interstitial Nephritis
• Drugs
• Obstruction
• Anuria - Obstruction until
proven otherwise
AKI: Pathogenesis
• Haemodynamic changes affecting
glomerular ultrafiltration.
• Ischaemia - Local
• Microvascular injury.
• Nephrotoxins.
• Predisposition • CKD, Cardiac Failure, DM
Prowle JR, et al. Nat Rev Nephrol 6, 107-15 (2010).
Nephron
Anatomy
O2
Tension
Blood
Flow
13
80%
6.6
10-15%
5-10%
1.5
AKI is a multifactorial process
affecting tubular function in areas of
baseline vulnerability
• Cardiac
• Vasodilatory
• Nephrotoxic
• ↓ RPP
• ↓ RPP
• Tubular Injury
• ↓ RBF
• →↑↓RBF
• Vasoconstriction
• ↓ GFR
• ↓ GFR
• Ischaemia
• Impaired
autoregulation
• Impaired
autoregulation
• Impaired
autoregulation
• Intra-renal
shunting
• Microvascular
injury in sepsis
OVERLAP
Nephrotoxins
• Direct cellular injury (Aminoglycosides,
Pigment, Contrast, Osmotic Injury)
• Vasoconstrictors (Contrast, NSAIDs, CNIs)
• Tubular obstruction (Urate, Acyclovir)
Events in endothelial cell activation, injury, and
reduced microvascular flow
Sharfuddin, A. A. & Molitoris, B. A. (2011) Pathophysiology of ischemic acute kidney injury
Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.16
Cellular Processes in AKI
Sharfuddin, A. A. & Molitoris, B. A. (2011) Pathophysiology of ischemic acute kidney injury
Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.16
Tubular Injury and GFR
Pathogenesis of AKI - Cases
• Case #1
• Severe sepsis
• Hyperdynamic shock
• high flow low pressure
• Altered microvascular
blood flow, endothelial
activation, microthrombi
and interstitial oedema
• Tubular injury
• Case #2
• Multifactorial
• Age-related CKD
• Hypotension with
inadequate cardiac
reserve
• Ischaemia
• Nephrotoxins
• Sepsis
AKI: Treatment
Prowle JR & Bellomo R: Acute
Kidney Injury: Specific
Interventions and Drugs.
In Management of Acute Kidney
Problems. Springer-Verlag,
2010, p. 229-239
Prowle JR & Bellomo R: Acute
Kidney Injury: Specific
Interventions and Drugs.
In Management of Acute Kidney
Problems. Springer-Verlag,
2010, p. 229-239
Late diagnosis prevents
effective treatment
• Ensure Adequate Cardiac Output
• Ensure Adequate Renal Perfusion Pressure
• Remove Nephrotoxins
• Avoid secondary injury
• Biomarkers of AKI
AKI: Therapy
Supportive treatment
Mechanisms involved in the renal responses to intravenous and renal artery
infusions of noradrenaline in conscious dogs.
Anderson WP, Korner PI, Selig SE J Physiol 1981, 321:21-30.
Norepinephrine or dopamine for the treatment of hyperdynamic septic shock?
Martin C, Papazian L, Perrin G, Gouin F: Chest 1993, 103:1826-1831
First do no harm!
Fluid Overload
Prowle JR, et al. Nat Rev Nephrol 6, 107-15 (2010).
Cases - Treatment
• Withdrawal of nephrotoxins
• Resuscitation to perfusion guided endpoint
• Cardiac index, Stroke volume, Lactate, ScvO2
• Noradrenaline to MAP 60 to 75
• Treat sepsis
• Avoid secondary injury
• Remain oliguric?
• Established tubular injury takes time to reverse
Renal Replacement
Therapy in the ICU
To maintain homeostasis while
patient and kidney function recovers.
Indications
• Refractory:
• hyperkalaemia
• acidaemia
• fluid overload
• uraemia
• oliguria
• dysnatraemia, toxin removal, temperature extremes, sepsis
• if possible in anticipation of emergent need
Indications for RRT in the
RENAL Study
N Engl J Med 2009; 361:1627-1638
• Oliguria (urine output <100 ml in a 6-hour period)
• unresponsive to fluid resuscitation measures
• Potassium concentration >6.5 mmol
• Severe acidemia (pH <7.2)
• Urea >25 mmol per liter
• Creatinine concentration >300 μmol per liter
• The presence of clinically significant organ edema
Cases: Indications for RRT
• Case #1
• Case #2
• UO 25ml/ml
• UO 5-10ml/hr
• Creat 300 Urea 22
• Creat 200 Urea 27
• Lactate 5 Bicarb 17
• Lactate 2 pH 7.34
• PaCO2 6.7 pH 7.15
• K+ 5.2
• K+ 5.8
• FB +7L yesterday
• Ventilated 60% O2
• Needing CPAP
PEEP 12 PaO2 8.6
• Albumin 19
• Ileus - Surgeon
suggests TPN
Requirements
• A Plan
• Machine
• A filter/dialyzer
• Nurse
• Adequate Vascular Access
• Blood pressure and Cardiac Output
• Replacement/Dialysis fluid
• Monitoring and point of care testing
• Anticoagulation
Semi-permeable membrane
First Practicable Dialyser - Kloff 1945
Sausage skin
Rotating Drum
Fluid bath
Modern CRRT Device
Membrane
Roller Pump
Fluid
Molecular movement across membrane
•Convection
–With bulk fluid movement
–Pressure gradient
•Diffusion
–Due to random movement in
solution
–Concentration gradient
–Molecular weight
–Thermal energy
Ultrafiltration with Convection
Diffusion
Ultrafiltration with Convection
Diffusion
Solute clearance
• Dialysis can be very efficient and effectively clear all small solutes
with a sufficient dialysate flow rate
– Requires a small amount of ultrafiltration equal to need for
fluid removal
• Convection (filtration) solute clearance is limited by amount of
filtration performed
– Blood cannot be totally cleaned as 100% of plasma cannot be
filtered
– significant removal of solute requires filtration above needs for
fluid removal necessitating use of a replacement solution
• Both therapies regularise electrolyte concentrations by using a
buffered salt solution as dialysate or replacement solution.
Dialysis vs Filtration
• Dialysis can be more efficient
• especially for small molecules
• Filtration can be more effective at removing
larger molecules, up to membrane cut-off
• but total clearances may be limited by
achievable filtration rate
• Haemodiafiltration or High Flux Continuous
Haemodialysis offer some of the benefits of both
Forms of Continuous Renal Replacement Therapy (CRRT)
Clearances on Continuous Therapy
Amount of fluid collecting in effluent bag
per min approximates clearance.
A Dose of 25ml/kg/hr is justified by
current evidence.
Trouble-shooting CRRT
• The nursing staff are the experts
• Adequate blood flow rate is essential
• Usually the vascath is the problem not the
anticoagulation
• Right line, right site, right length
• RIJ>Femoral>LIJ
• Avoid SCV if possible
• Need 24cm+ lines for femoral
Summary
• Early diagnosis of AKI is difficult
• Pathogenesis is multifactorial
• Maintain CO, BP and remove
nephrotoxins
• Do no harm
• Supportive RRT if indicated
• CRRT in the ICU
Oh, dear God! This man's kidney's have exploded!
There's nothing left!