October 2010
Acute Kidney Injury
Michael Clarkson
Department of Renal Medicine
Cork University Hospital
“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
October 2010
Terminology
Acute Renal Failure (ARF)
Acute Kidney Injury (AKI)
Acute Tubular Necrosis (ATN)
May 2007 AKI for the General Physician
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
R.I.F.L.E. R ISK
I NJURY
F AILURE
L OSS
E SKD
October 2010
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 <0.3 ml/kg/hr x 24h [Creat] > 350 umol/l anuria x 12h
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
I
↑ 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/Lor RRT
Urine output < 0.3 ml/kg/hour for > 24 hours or anuria for 12 hours
October 2010
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.
Consequences of AKI
Acute metabolic complications Acute cardiovascular complications Prolonged hospitalisation Resource consumption
Patient Death Common ESKD Uncommon
October 2010
Epidemiology
October 2010
Madrid Acute Renal Failure StudyLiano F; Pascual J. Kidney Int 1996; 50: 811-8
Prospective, multi-centre, community-based 9 month period Creatinine >177mol/L 13 hospitals (4.2 million aged >14yrs)
209(195,223) cases pmp48% normal function at admission36% received RRT45% hospital mortality
October 2010
What kind of AKI? (Madrid Study)
0%10%20%30%40%50%60%70%80%90%
100%
ICU (n=253) Non-ICU (n=495)
Other
Atheroemboli
GN
AIN
Obstruction
Acute-on- Chronic
PreRenal
ATN
October 2010
Uchino S, Kellum JA, Bellomo R, et al. Acute Renal Failure in Critically Ill Patients: A Multinational Multicentre StudyJAMA 2005;294: 813-818.
BEST Kidney Investigators
54 Study Centres, 23 Countries, 15 months ~30 000 ICU admissions
5.5 to 6.0% AKI (<200ml/12h; [urea]>30mmol/l) 4.0 to 4.4% RRT (80% CRRT)
30% pre-existing renal dysfunction
October 2010
Uchino S, Kellum JA, Bellomo R, et al. Acute Renal Failure in Critically Ill Patients: A Multinational Multicentre StudyJAMA 2005;294: 813-818.
58.9
13 11.3 10.1 10
41.1
23.2
11.4
0
10
20
30
40
50
60
70
%
MedicalRespiratoryCardiovascularGastrointestinalSepsisSurgicalCardiovascularGI Tract
October 2010
Uchino S, Kellum JA, Bellomo R, et al. Acute Renal Failure in Critically Ill Patients: A Multinational Multicentre StudyJAMA 2005;294: 813-818.
ICU mortality 52% Subsequent hospital mortality 8%
Total mortality 58-62.5% SAPS-II predicted 45.6%
Independent of dialysis 83.7-88.8%
Septic shock, vasopressors, mechanical ventilation, HRS
October 2010
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 / Contrast / Post-op / Sepsis / Non-renal Tx
Medications Aminoglycosides>NSAID>Pip-Tazo>Ampho>SMX-
TMP>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)
36
14 1310 9
0
10
20
30
40
Obstruction Surgical Cardiovascular Sepsis ECF Depletion
% o
f ca
ses
October 2010
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.
CVP / fluid status
Urinalysis
Ultrasound
36 month survival
0
10
20
30
40
50
%
3 assmt2 assmt1 assmt0 assmt
October 2010
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
Exogenous Toxins Radiocontrast Aminoglycosides Cisplatin
October 2010
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 230mol/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 stuff3. Don’t be too rough4. Don’t keep clotting5. Don’t keep bleeding6. Don’t be too
expensive7. Don’t be too
complicated
October 2010
Some Physics (the fundamentals)
Haemodialysis
Solute removal by
Diffusion
Haemofiltration
Solute removal by
Convection
October 2010
What kind of RRT…….?
Diffusion
Haemodialysis
FastSometimes not well toleratedSmall moleculesClearance of drugs variableRequires dialysis expertise
Convection
Haemofiltration
SlowUsually well toleratedMedium-sized moleculesClearance of most drugsCan be ‘run’ with less
knowledge/expertiseMore 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 RR 0.96 (0.85-1.05)• Renal death RR 1.02 (0.85-1.08)• ESKD RR 1.02 (0.89-1.17)
October 2010
Kellum JA, et al. Continuous versus intermittent renal replacement therapy: a meta-analysis.Intensive Care Med 2002; 28: 29-37
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 RR 0.93 (0.79, 1.09) Adjusted for quality RR 0.72 (0.60, 0.87) Similar severity RR 0.48 (0.34, 0.69)
October 2010
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
How much?
How often?
Renal Replacement Therapy
October 2010
May 2007 AKI for the General Physician
Specific therapies for ATN
Diuretics
Dopamine / Fenoldopam
ANP / ANP analogues
Growth factors
October 2010
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 Placebo
Survival/renal recovery No difference 2litre diuresis achieved 57% v 33%
Mehta RL, et al; PICARD Study GroupDiuretics, mortality, and non-recovery of renal function in acute renal failure. JAMA 2002; 288: 2547-53.
Uchino S, et al; BEST Kidney Investigators Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32: 1669-77.
Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failureBMJ 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.
1966-2000 Prevention/Treatment
58 (n=2149) studies 24 (n=1019) outcome 17 (n= 854) RCT
Mortality 0.44-1.83
AKI 0.55-1.19
RRT 0.55-1.24Power for >50% effect on AKI/RRT
October 2010
May 2007 AKI for the General Physician
Renal-dose dopamine: from hypothesis to paradigm to dogma to myth and, finally, superstition?
Jones D, Bellomo RJ Intensive Care Med 2005;20: 247-8
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
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
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