Acute Kidney Injury
Michael Clarkson
Department of Renal
Medicine
Cork University Hospital
October 2010
“Acute Renal Failure”


Syndrome is not dichotomous
Dynamic process



initiation, maintenance and recovery phases.
Undue emphasis on whether or not renal
function has overtly failed.
Minor decrements in glomerular filtration
associated with adverse clinical
outcomes.
October 2010
Terminology
Acute Renal Failure (ARF)
Acute Kidney Injury (AKI)
Acute Tubular Necrosis (ATN)
October 2010
Bellomo R, Ronco C, Mehta RL, Palevsky P; ADQI workgroup.
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.
Crit Care 2004; 8:R204-12.
www.ADQI.net
May 2007
AKI for the General Physician
R.I.F.L.E.
October 2010

R ISK

I NJURY

F AILURE

L OSS

E SKD
Levels for definition

R
[Creat] x 1.5
<0.5
ml/kg/h
x 6h

I
[Creat] x 2.0
<0.5
ml/kg/hr
x 12h

F
[Creat] x 3.0
[Creat] > 350
<0.3 ml/kg/hr
anuria
x 24h
x 12h
umol/l

L
complete loss of function
> 4 weeks

E
End Stage Kidney Disease
> 13 weeks
October 2010
AKI Network Definition
AKI stage
Creatinine criteria
Urine output
criteria
↑ by >/= 25 µmol/L or
↑ to >/= 150% – 200%
Urine output < 0.5
ml/kg/hour for > 6
hours
II
↑ > 200% – 300% from
baseline
Urine output < 0.5
ml/kg/hour for > 12
hours
III
↑> 300% or Creat>/=
350 µmol/L after a rise
of at least 50µmol/L
or RRT
Urine output < 0.3
ml/kg/hour for > 24
hours or anuria for
12 hours
I
RIFLE Criteria - Validity

The outcome of acute renal failure in the intensive
care unit according to RIFLE: model application,
sensitivity, and predictability. Abousaif et al. AJKD
2005.

RIFLE criteria for acute kidney injury are associated
with hospital mortality in critically ill patients: a cohort
analysis. Hoste et al. Crit Care 2005.

An assessment of the RIFLE criteria for acute renal
failure in hospitalized patients. Uchino et al. Crit Care
Med. 2006.
October 2010
Consequences of AKI






Acute metabolic complications
Acute cardiovascular complications
Prolonged hospitalisation
Resource consumption
Patient Death
ESKD
October 2010
Common
Uncommon
Epidemiology
October 2010
Madrid Acute Renal Failure Study
Liano F; Pascual J. Kidney Int 1996; 50: 811-8




Prospective, multi-centre, community-based
9 month period
Creatinine >177mol/L
13 hospitals (4.2 million aged >14yrs)
209(195,223) cases pmp
48% normal function at admission
36% received RRT
45% hospital mortality
October 2010
What kind of AKI?
(Madrid Study)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Other
Atheroemboli
GN
AIN
Obstruction
Acute-on- Chronic
PreRenal
ATN
ICU (n=253)
October 2010
Non-ICU (n=495)
Uchino S, Kellum JA, Bellomo R, et al.
Acute Renal Failure in Critically Ill Patients:
A Multinational Multicentre Study
JAMA 2005;294: 813-818.

BEST Kidney Investigators

54 Study Centres, 23 Countries, 15 months
~30 000 ICU admissions


5.5 to 6.0% AKI
4.0 to 4.4% RRT

30% pre-existing renal dysfunction

October 2010
(<200ml/12h; [urea]>30mmol/l)
(80% CRRT)
Uchino S, Kellum JA, Bellomo R, et al.
Acute Renal Failure in Critically Ill Patients:
A Multinational Multicentre Study
JAMA 2005;294: 813-818.
70
60
58.9
%
50
41.1
40
30
20
10
0
October 2010
23.2
13
11.3 10.1
10
11.4
Medical
Respiratory
Cardiovascular
Gastrointestinal
Sepsis
Surgical
Cardiovascular
GI Tract
Uchino S, Kellum JA, Bellomo R, et al.
Acute Renal Failure in Critically Ill Patients:
A Multinational Multicentre Study
JAMA 2005;294: 813-818.


ICU mortality
Subsequent hospital mortality
52%
8%

Total mortality
SAPS-II predicted

Independent of dialysis

Septic shock, vasopressors, mechanical ventilation, HRS

October 2010
58-62.5%
45.6%
83.7-88.8%
Nash K, Hafeez A, Hou S.
Hospital-Acquired Renal Insufficiency.
AJKD 2002;39(5): 930-6

4622 consecutive patients. Tertiary
Referral Hospital.

AKI 7.2%

Risk Factors: CKD, Age, Race.
October 2010
Nash K, Hafeez A, Hou S.
Hospital-Acquired Renal Insufficiency.
AJKD 2002;39(5): 930-6

Causal Factors

Renal Hypoperfusion
• ECV, CHF, BP


Medications


Medications / Contrast / Post-op / Sepsis / Non-renal
Tx
Aminoglycosides>NSAID>Pip-Tazo>Ampho>SMXTMP>Cya
Outcome

Complete recovery 38%, Death 20%, HD 4%, CKD
38%
October 2010
Causes of Severe AKI
Feest TG, Mistry CD, Grimes DS, Mallick NP.
(from RA Study on Incidence of CRF)
40
36
% of cases
30
20
14
13
10
10
9
0
Obstruction
October 2010
Surgical
Cardiovascular
Sepsis
ECF Depletion
Treatment
October 2010
How should AKI be treated..?

General therapy

Prevention

Specific therapy

RRT
October 2010
How should AKI be treated..?

General Measures
Discontinue offending agents
 Avoid nephrotoxins if possible
 Forensic attention to current / previous
Rx
 Meticulous attention to assessment of
ECV status

October 2010
P.E. Stevens, et al.
Non-specialist management of acute renal failure.
QJM 2001; 94: 533-40

East Kent (593 000)
12 month prospective study
486 cases p.m.p. [Creat]>300umol/l

Focus on initial assessment/management


October 2010
Rayner HC.
A model undergraduate core curriculum in adult renal medicine.
Med Teacher 1995; 17:409–2.
36 month survival

50
CVP / fluid status
40
Urinalysis
%

30
20

Ultrasound
10
0
October 2010
3 assmt
2 assmt
1 assmt
0 assmt
AKI – Minimum Data Set






Serial assessment / record of ECV status
Renal profile, Ca2+, PO4-, ABG
Urinalysis / urine output
Nephrotoxic medication review
Renal Ultrasound
Focused investigations (vasculitis,
myeloma, uric acid, CPK etc.)
October 2010
Prevention of AKI
Prevention of AKI
Optimisation of ECV is single most
important manoeuvre
 Volume depletion is risk factor for
AKI in multiple clinical situations


Endogenous Toxins



Myoglobin
Light chains
Uric Acid
October 2010

Exogenous Toxins



Radiocontrast
Aminoglycosides
Cisplatin
Which fluid?
Crystaloid vs. Colloid
Schierhout G et al. Fluid resuscitation with colloid or
crystalloid solutions in critically ill patients: a
systematic review of randomized trials.
BMJ 1998;316:961-4.




37 RCTS
 26 colloids vs. crystalloids (n = 1622).
 10 colloid in hypertonic crystalloid vs. isotonic
crystalloid (n = 1422)
 1 colloid in isotonic crystalloid with hypertonic
crystalloid (n = 38)
Mortality RR 1.19
(0.98-1.45)
No benefit from colloid
Cost more.
October 2010
Finfer S et al. A comparison of albumin and saline for
fluid resuscitation in the intensive care unit.
N Engl J Med 2004;350:2247-56.

Saline versus Albumin Fluid Evaluation (SAFE) Study
16 ICUs in Australia and New Zealand. n=6997
4% Albumin vs. 0.9% NaCl

Outcomes:



28 Day Mortality
RR 0.99 (0.91-1.09)

Days of RRT:
Not significant
October 2010
Schortgen, F et al. Effects of hydroxyethylstarch and
gelatin on renal function in severe sepsis: a multicentre
randomised study. Lancet 2001;357:911-16.

6% hydroxyethylstarch or 3% fluid-modified gelatin.
RCT, n=129

Acute renal failure



RR 2·32 (CI 1·02–5·34).
6% hydroxyethylstarch is an independent risk factor
for development of AKI
Do not use!
October 2010
Rivers E, et al.
Early goal-directed therapy in the treatment of severe
sepsis and septic shock. N Engl J Med 2001;345:1368-77

‘Goal-directed’ resuscitation in sepsis.

Mean creatinine 230mol/L on admission.

Defined hemodynamic targets:
 MAP > 65mmHg,
 CVP 10-12,
 Urine output>0.5mls/kg/hr,
 ScvO2>70%).

Significant decrease in mortality.
October 2010
Renal Replacement Therapy
October 2010
Please, Sir…..what’s the
prescription….?
1. Remove the bad
stuff
2. Leave the good stuff
3. Don’t be too rough
4. Don’t keep clotting
5. Don’t keep bleeding
6. Don’t be too
expensive
7. Don’t be too
complicated
October 2010
Some Physics (the
fundamentals)
Haemodialysis
Haemofiltration
Solute removal by
Solute removal by
Diffusion
Convection
October 2010
What kind of RRT…….?
Diffusion
Convection
Haemodialysis
Haemofiltration
Fast
Sometimes not well tolerated
Small molecules
Clearance of drugs variable
Requires dialysis expertise
Slow
Usually well tolerated
Medium-sized molecules
Clearance of most drugs
Can be ‘run’ with less
knowledge/expertise
More expensive !!!!!!!!!!!!!
October 2010
Intermittant HD vs. CRRT

Swartz, et al.
Comparing continuous haemofiltration with hemodialysis in
patients with severe acute renal failure.
Am J Kidney Dis 1999; 34: 424-32

Mehta, et al.
A randomized clinical trial of continuous versus intermittent
dialysis for acute renal failure.
Kidney Int 2001; 60:1154-63.

Uehlinger, et al.
Comparison of continuous and intermittent renal replacement
therapy for acute renal failure.
Nephrol Dial Transplant 2005;20:1630-7.
October 2010
Tonelli, et al.
Acute renal failure in the intensive care unit: a systematic
review of the impact of dialytic modality on mortality and
renal recovery. Am J Kidney Dis 2002;40:875-85
6 RCTs
 CRRT vs. HD
 N=624

• Mortality
• Renal death
• ESKD
October 2010
RR 0.96 (0.85-1.05)
RR 1.02 (0.85-1.08)
RR 1.02 (0.89-1.17)
Kellum JA, et al.
Continuous versus intermittent renal replacement therapy: a metaanalysis.
Intensive Care Med 2002; 28: 29-37

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Randomised & Observational Studies
CRRT v HD
Primary end-point RR cumulative mortality
13 studies (3 randomised) – 1400 patients
Poor quality – only 6 corrected for severity
Overall
Adjusted for quality
Similar severity
October 2010
RR 0.93 (0.79, 1.09)
RR 0.72 (0.60, 0.87)
RR 0.48 (0.34, 0.69)
Renal Replacement Therapy

Choice often dictated by…

Resources of the institution
• CVVH not available

Technical expertise of the physician
• Intensivist vs. nephrologist

Clinical status of the patient
• Cerebral edema
• Bleeding risk
October 2010
Renal Replacement Therapy

How much?

How often?
October 2010
Specific therapies for ATN

Diuretics

Dopamine / Fenoldopam

ANP / ANP analogues

Growth factors
May 2007
AKI for the General Physician
Cantarovich F, et al.
High-dose furosemide for established ARF: a prospective,
randomized, double-blind, placebo-controlled, multicenter trial.
Am J Kidney Dis. 2004; 44: 402-9.


338 AKI patients, stratified by severity
25mg/kg/day iv or 35mg/kg/day po
v

Survival/renal recovery
2litre diuresis achieved

Mehta RL, et al; PICARD Study Group

No difference
57% v 33%
Diuretics, mortality, and non-recovery of renal function in
acute renal failure.
JAMA 2002; 288: 2547-53.

Placebo
Uchino S, et al; BEST Kidney Investigators
Diuretics and mortality in acute renal failure.
Crit Care Med 2004; 32: 1669-77.
October 2010
Ho KM, Sheridan DJ.
Meta-analysis of frusemide to prevent or treat acute renal failure
BMJ 2006; 333:420.

9 RCTs

849 patients

In-hospital mortality, RRT, number of RRT
treatments, persistent oliguria

No benefit

Deafness and tinnitus (RR 1.00,15.78)
October 2010
Diuretics in AKI

Diuretics are not nephrotoxic

Doctors prescribing habits are
nephrotoxic!
October 2010
Kellum JA, Decker JM.
Use of dopamine in acute renal failure: a meta-analysis.
Crit Care Med 2001; 29: 1526-31.

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1966-2000
Prevention/Treatment
58 (n=2149) studies
24 (n=1019) outcome
17 (n= 854) RCT
October 2010

Mortality 0.44-1.83

AKI
0.55-1.19

RRT
0.55-1.24
Power for >50% effect on AKI/RRT
Renal-dose dopamine: from
hypothesis to paradigm to
dogma to myth and, finally,
superstition?
Jones D, Bellomo R
J Intensive Care Med 2005;20: 247-8
May 2007
AKI for the General Physician
Other Pharmacotherapies

Recombinant Growth Factors
• Maybe good if you are small, white & furry with a
long tail
• Not so good if you are anything else

Calcium Channel Blockers
• No RCT suggest benefit
• Risk hypotension

Theophyline
• No RCT suggest clinically important benefit
• Narrow therapeutic window
October 2010
Is there hope……………?
October 2010
If I end up in your ICU with AKI………….

There is no pharmacologic treatment for established ATN

Excellence in generic supportive management

If you give me dopamine or thoughtlessly prescribed
diuretics I’ll sue you
(I mean, haunt you………..)

Adequate dose CVVH

Intermittent HD only by an expert

My kidneys will get better if I do
October 2010