ARF No ATN Data
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acute renal failure…from basics to the latest advances
Joel M. Topf, MD
Clinical Nephrologist
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the housemoment
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Dr. Haas invented the first dialysis machine designedfor humans and in 1928 he treated 6 patients.
All of them died.
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In 1943, Willem Kolff’s, working in theNazi occupied Netherlands createdthe second human dialysis machine.
In 1943 he dialyzed his first patient, ayoung man with acute nephritis.
In 1945, a 67-year-old woman inuremic coma presented to Dr Kolff.
Dr. Haas
Regained consciousness after 11hours of hemodialysis.
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Commonly quotedmortality of 70% isfor dialysis requiringICU patients
For hospital acquiredARF: 20%
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37 year old AA female
Multiple GSW
Prolonged hypotension
Aorta was crossclamped duringexploratory laparotomy
Anuric x 18 hours
Cr from 0.8 to 2.2
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36 y.o. African Americanwomen with menorrhagia.
Has prolonged bleedingfollowing fibroidectomy
Contrasted CT scan used todetermine source ofbleeding.
Cr rises from 0.8 to 2.2
Patient is non-oliguric
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Same rise in creatinine.
Same diagnosis: acute renal failure.
Two completely different diseases.
Two women.
Same age.
Same race.
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definition of acute renal failure
“Acute and sustained reduction in renal function.”
35 definitions
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Contrast nephropathyARF is defined by a 0.5mg/dL or 25% increase
in serum creatinine
biochemicaldefinitions
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Dialysis dependentARF is often used inretrospective cohorts Easy to capture
Unambiguous
Important end-point
event drivendefinitions
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R isk
I njury
F ailure
L oss of function
E nd-Stage Renal disease
rifle criteria forstratifying arf
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R isk
Increase in Cr of 1.5-2.0 X baseline or
urine output < 0.5 mL/kg/hr for more than 6 hours.
I njury
F ailure
L oss of function
E nd-Stage Renal disease
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R isk: Inc Cr 50-100% or U.O. < 0.5 mL/kg/hr for > 6 hrs
I njury
increase in Cr 2-3 X baseline (loss of 50% of GFR) or
urine output < 0.5 mL/kg/hr for more than 12 hours.
F ailure
L oss of function
E nd-Stage Renal disease
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R isk: Inc Cr 50-100% or U.O. < 0.5 mL/kg/hr for > 6 hrs
I njury: Inc Cr 100-200% or U.O. < 0.5 mL/kg/hr > 12 hrs
F ailure
increase in Cr rises > 3X baseline Cr (loss of 75% of GFR) or
an increase in serum creatinine greater than 4 mg/dL, or
urine output < 0.3 mL/kg/hr for more than 24 hours oranuria for more than 12 hours.
L oss of function
E nd-Stage Renal disease
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R isk: Inc Cr 50-100% or U.O. < 0.5 mL/kg/hr for > 6 hrs
I njury: Inc Cr 100-200% or U.O. < 0.5 mL/kg/hr > 12 hrs
F ailure: Inc Cr > 200% or > 4 mg/dL or U.O. < 0.3 mL/kg/hr >
24 hrs or anuria for more than 12 hours
L oss of function
persistent renal failure (i.e. need for dialysis) for more than 4weeks.
E nd-Stage Renal disease
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R isk: Inc Cr 50-100% or U.O. < 0.5 mL/kg/hr for > 6 hrs
I njury: Inc Cr 100-200% or U.O. < 0.5 mL/kg/hr > 12 hrs
F ailure: Inc Cr > 200% or > 4 mg/dL or U.O. < 0.3 mL/kg/hr >
24 hrs or anuria for more than 12 hours
L oss of function: Need for dialysis for more than 4 weeks
E nd-Stage Renal disease
persistent renal failure (i.e. need for dialysis) for more than 3months.
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R isk: Inc Cr 50-100% or U.O. < 0.5 mL/kg/hr for > 6 hrs
I njury: Inc Cr 100-200% or U.O. < 0.5 mL/kg/hr > 12 hrs
F ailure: Inc Cr > 200% or > 4 mg/dL or U.O. < 0.3 mL/kg/hr >
24 hrs or anuria for more than 12 hours
L oss of function: Need for dialysis for more than 4 weeks
E nd-Stage Renal disease : Need for dialysis for more than 3
months
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nice criteria. do they work?
20,126 consecutiveadmissions to auniversity hospital Excluded kids
Kidney transplant anddialysis patients
Patients admitted for <24 hours
Using RIFLE: Risk 9.1%
Injury 5.2%
Failure 3.7%
Uchino S, Bellomo R, Goldsmith D. Crit Care Med 2006 Vol 34 1913-1917.
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>3x
BL
Cr
Cr >
4
Hos
pita
l Mor
talit
y
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nice criteria. do they work in the icu?
University of Pittsburghhas 7 ICUs
5,383 patients Excluded dialysis
Subsequent admissions
Frequency of acuteKidney failure: No AKD 1,766
Risk 670
Injury 1,436
Failure 1,511
Hoste E, Clermont G, Kersten A. Crit Care 2006 Vol 310
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when Hoste looked at markers ofseverity of illness excluding the renalsystem:
No survival difference between the4 groups:
• Lack of renal failure• Risk• Injury• Failure
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RIFLE is dependent on creatinine.creatine is a functional marker oforgan damage
Functionalmarkers: oldand busted
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biomarkers are foot prints of actualorgan damage
Biomarkers,new hotness
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functional versus biomarkers
SGOT
SGPT
GGT
Hypoalbuminemia
CoagulopathyLiver damage
BiomarkerFunctionalMarker
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functional versus biomarkers
Troponin I
Troponin T
CK-MB
Hypotension
ArrhythmiaHeart damage
SGOT
SGPT
GGT
Hypoalbuminemia
CoagulopathyLiver damage
BiomarkerFunctionalMarker
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functional versus biomarkers
KIM-1
NGAL
Creatinine
BUN
Cystatin CKidney damage
Troponin I
Troponin T
CK-MB
Hypotension
ArrhythmiaHeart damage
SGOT
SGPT
GGT
Hypoalbuminemia
CoagulopathyLiver damage
BiomarkerFunctionalMarker
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creatinine as a lagging indicator
4,118 Cardiac surgery patients
Prospectively looked at changes of creatinine48 hours post-op on 30-day mortality
All odds ratios were controlled for 26variables found to be significant predictors ofmortality in univariate analysis
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<0.5 0.4 0.2 0.1 0.3 0.5 0.7 0.9
Creatinine falls Creatinine rises
Delta Creatinine (mg/dL)
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candidates for a renal troponin:
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Transmembraneprotein expressedin the proximaltubule.
Expression isincreasedfollowing ischemicdamage
Can be found 12hours after renalinsult
2.00
0.34
0.13
0.69
Han WH, Bailly V, Abichandani. Kidney Int 2002 62, 237–244.Liangos O, Han WK, Wald R. Abstract J Am Soc Nephrol 16: 318A, 2005.
candidates for a renal troponin:kidney injury molecule-1 (kim-1)
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candidates for a renal troponin:kidney injury molecule-1 (kim-1)
Transmembraneprotein expressedin the proximaltubule.
Expression is inc-reased followingischemic damage
Can be found 12hours after renalinsult
Time starts at aorta crossclamp. Cr rose to 2.1.
Han WH, Bailly V, Abichandani. Kidney Int 2002 62, 237–244.Liangos O, Han WK, Wald R. Abstract J Am Soc Nephrol 16: 318A, 2005.
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Mishra J, Ma Q, Prada A. J Am Soc Nephrol 2003; 14: 2534-43.Wagener G, Jan M, K M. Anesthesia 2006; 105: 485-91.
urinary neutrophil gelatinase-associated lipocalin (ngal)
Protein that is secretedby the kidney in res-ponse to ischemic injury
Early data in childrenshowed nearly perfectsensitivity andspecificity
False positives with UTI
Prospectiveobservational trial
81 adults going forCardiac surgery 65 No AKI
1 died of MOF
16 AKI (Risk or higher)5 required CVVH
5 died of MOF
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differential diagnosis
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etiologies of arf
Seventy percent have concurrent oliguria < 400 mL/day
< 0.5 mL/kg/hr in children
< 1 mL/kg/hr in infants
Complicates 5-7% of hospitalizations
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Hou SH, Bushinsky DA, Wish JB. Am J Med 1983; 74: 243-8.Nash K, Hafeez A, Hou S. Am J Kidney Dis. 2002; 39: 930-6.
Kaufman J, Dhakal M, Patel B, Et al. Am J Kidney Dis 1991; 17: 191-8.
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Hou SH, Bushinsky DA, Wish JB. Am J Med 1983; 74: 243-8.Nash K, Hafeez A, Hou S. Am J Kidney Dis. 2002; 39: 930-6.
Kaufman J, Dhakal M, Patel B, Et al. Am J Kidney Dis 1991; 17: 191-8.
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N=103N=256N=389
Pascual J, Liano F. J Am Geriatr Soc 1998, 46: 1-5.
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hospital acquired acute renal failure
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hospital acquired acute renal failure
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Pre-renal azotemiaNo BP, no pee pee
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GFR
Pre-renal ARF
Properly functioning kidney, properlyresponding to a drop in systemic and renalperfusion
no bp, no pee pee
RPF
a u t o r e g u l a t i o n
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differentiation of prerenal fromintrinsic renal disease
Use of FENa Fraction of filtered sodium which is excreted in the
urine.
Patients with prerenal azotemia will be sodiumavid and minimize renal excretion of sodiumlowering the FENa below 1%
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Excreted NaFiltered Na
Fractional excretion ofsodium:
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Excreted Na = Urine Na x Urine Volume
Calculating the Numerator
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GFR = Urine Cr x Urine Volume Serum Cr
Filtered Na = Serum Na x GFR
Filtered Na = Serum Na x UrCr x UrVol Serum Cr
Calculating the Denominator
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Excreted NaFiltered Na
FENa =
Urine Na x Urine VolumeSerum Na x UrCr x Urine Volume
Serum CrFENa =
Urine NaSerum Na x UrCr Serum Cr
FENa =
Urine Na x Serum CrSerum Na x UrCr
FENa =
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Sr Na
Ur Na Ur Cr
Sr Cr
Sr Na
Sr Cr x Ur Na
x Ur CrFENa =
FENa the easy way
FENa is a small number 0.1% to 3%
So the calculation will be 0.001-0.03 prior toconverting to percent by X 100
So make the fraction small by putting the smallnumbers over the big numbers
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FeNa. what is it good for?
The discriminator for differentiating between prerenal azotemiaand ATN is 1%:
FENa < 1 indicates pre-renalazotemia
Sensitivity: 90%
Specificity: 93%
FENa > 1 indicates ATN
Sensitivity: 93%
Specificity: 90%
513FENa > 1
427FENa < 1
ATN (oliguric andnon-oliguric)
Pre-renalazotemia
427FENa < 1
513FENa > 1
ATN (oliguric andnon-oliguric)
Pre-renalazotemia
Miller, Schrier, Et al. Annals Int Med, 1978 Vol 89. p 47-50
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FENa False PositiveLow FENa, Not pre-renal
Pre-renal Azotemia
Contrast Nephropathy
Hemoglobinuricnephropathy
Myoglobinuric nephropathy
Acute rejection
Cyclosporin and Tacrolimustoxicity*
Hepatorenal syndrome
Acute interstitial nephritis
ATN tested too early
ATN with CHF
ATN with cirrhosis
ATN with severe burns
Non-oliguric acute renalfailure
Acute Glomerulonephritis
ACEi in bilateral RAS or inRAS with solitary kidney
NSAID induced ARF
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FeNa false negatives
Diuretics Metabolic alkalosis
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Patients with a decreased FENa were testedearlier than those with an elevated FENa 1.7 days for the low FENa group
3.4 days for the high FENa group
70% of patients in the low FENa group had asubsequent FENa > 1%
Low fractional excretion of sodium in acuterenal failure
Role of timing of the test and ischemia
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Kaplan, Kohn. American J Nephrol, 1992; 12: 49-54.
fractional excretion of urea
Based on the physiologic increase in ureareabsorption with pre-renal azotemia
Normal FE Urea is 50-65% in well hydratedindividuals
In prerenal azotemia this falls below 35%
Not affected by diuretics
Sr Na
Sr Cr x Ur Na
x Ur CrFENa =
Sr Urea
Sr Cr x Ur Urea
x Ur CrFEurea =
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Carvounis, Sabeeha, Nisar, Et al. Kidney Int, 2002 Vol 62. p 2223-2229
FEurea in the differential diagnosisof atn
102 patients with ARF
Gold standard was consultants full analysisand retrospective analysis of response totreatment.
Divided the cases into: ATN
Prerenal without diuretic
Prerenal treated with diuretics
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FENa
FEUrea
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therapy
Renal replacement therapy
Furosemide
Dopamine
Fenoldapam
hANP (Anaritide)
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renal replacement therapy
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Dialysate
1365.8
10817
67
3.8
1452
11035
0
0
Conventional DialysisDiffusive Clearance
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1365.8
10817
67
3.8
1365.8
10817
67
3.8
80 mmol K5.8 mmol/L
= 13.8 litersIsolated Ultrafiltration: CHF SolutionsMinimal clearance
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Ultrafilter 3+ liters/hour
Replace all ultrafiltratewith sterile fluid at idealplasma concentrations
1365.8
10817
67
3.8
140 2
10830
0
0
140 4
10830
0
0
CVVHConvective clearance
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Post-filter replacement fluid
CVVHConvective clearance
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Pre-filter replacement fluid
CVVHConvective clearance
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CVVHDFConvective and Diffusive
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high dose dialysissu
rvival
Severity of illness (CCARF Score)
High dose
Low dose
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Ronco’s landmark dialysis dosestudy
425 patients with dialysis dependent acuterenal failure were randomized to one of threedoses of CVVH 20 mL/kg/hr of effluent
35 mL/kg/hr
45 mL/kg/hr
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20 mL/kg/hr
35 mL/kg/hr
45 mL/kg/hr
Ronco C, Bellomo R, Hormea P, Et al. Lancet 2000; 355: 26-30.
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Schiffl: daily dialysis versus threedays/wk dialysis
160 patients
Schiffl, H. et al. N Engl J Med 2002;346:305-310
P=0.01 P=0.001
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Schiffl, H. et al. N Engl J Med 2002;346:305-310
P=0.002
P=0.005P=0.007
P=0.02
odds ratio of death
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adding dialysis to CVVH
206 dialysis patients randomized to CVVH 1-2.5 L/hr
CVVH plus 1-1.5 liters of dialysate (CVVHDF)
P=0.03 P=0.008
Saudin P, Niederberger S, De Seigneux S, Et al. Kidney Int 2006; 70: 1312-7.
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Ronco 425 CVVH 20/h vs. 35-45 ml/kg/h*
Bouman 106 CVVH 20ml/kg/h* vs. 48 ml/kg/h
Schiffl 160 Alternate day vs. daily hemodialysis
Saudan 206 CVVH 25 ml/kg/h vs. CVVHDF 42 ml/kg/h
Total (fixed effects)
Total (random effects)
1 10Odds ratio
Study n treatment groups
*For purposes of analysis the two high-dose arms in Ronco were combined, as were the two low-dose arms inBouman. If these groups are removed the odds ratio is unchanged (1.94; P <0.001).
Kellum J. Nature Clin Practice Nephrol 2007 3: 128-9.
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future data
US trial: ATN Primarily veterans hospital
Prospective randomized, multi-center trial
Dose finding studyConventional daily dialysis
SLED
CVVH
CVVHD
CVVHDF
Australian trial: RENAL
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furosemide
Decreased activity of the ascending loop ofHenle decreases renal oxygen demand by thekidney Better align demand and supply in ischemia
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Mehta’s trial of furosemide in arf
Mehta, R. L. et al. JAMA 2002;288:2547-2553.
Retrospective review ofICU patients
Diuretic responsivenessdetermined survival
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furosemide the rct
338 with dialysis dependent ARF
Randomized to high dose furosemide (2,000mg/day) vs placebo
End-point length of dialysis
No improvement of survival, length ofdialysis, number of dialysis sessions
Shorter time to 2 liters/day of urine output
Cantarovich F, Rangoonwala B, Et al. Am J Kidney Dis 2004; 44: 402-9.
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dopamine: still doesn’t work
In healthy volunteers lowdose dopamine increasesrenal blood flow andinduces diuresis
Patients in the intensivecare unit do not respondthis way.
Increased RBF
Increased urine
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dopamine: still doesn’t work
In healthy volunteers lowdose dopamine increasesrenal blood flow andinduces diuresis
Patients in the intensivecare unit do not respondthis way. RCT of 380 ICU patients
with early renal failure
ANZICS Clinical Trials Group. Lancet 2000;356:2139-47.Kellum JA, Decker JM.Crit Care 2001; 29:1526-31.
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dopamine: still doesn’t work
In healthy volunteers lowdose dopamine increasesrenal blood flow andinduces diuresis
Patients in the intensivecare unit do not respondthis way. RCT of 380 ICU patients
with early renal failure
Meta-analysis of 58 studiesand 2,149 patients
ANZICS Clinical Trials Group. Lancet 2000;356:2139-47.Kellum JA, Decker JM.Crit Care 2001; 29:1526-31.
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dopamine: the randomizedcontrolled trial
328 ICU patients with SIRS
Early signs of renal failure < 0.5 cc/kg/hr
Cr > 1.7 mg/dL without a prior history of renaldisease
A rise in serum Cr of 0.9 mg/dL in less than 24hours
The primary outcome was peak serumcreatinine
ANZICS Clinical Trials Group. Lancet 2000;356:2139-47.
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Secondary end points: Furosemide dose 192 mg vs 268 mg p=0.39
Duration of mechanical ventilation 10 vs 11 p=0.63
Duration of ICU stay 13 vs 14 p=0.67
Survival to hospital discharge 92 vs 97 p=0.66
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Kellum JA, Decker JM.Crit Care 2001; 29:1526-31.
meta-analysis
Kellum and Decker searched MedLine(English and non-English literature) for everyarticle on human trials with dopamine for thetreatment or prevention of ARF from 1966 to1999.
They included 58 studies with 2149 patients
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A. Exclude radiocontraststudies
B. Limited to heart studies
C. Excludes studies inwhich had abnormalcontrol groups orincreased variance
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Dopamine increases cortical blood flow morethan medullary blood flow Cortical blood flow increases GFR
Cortical blood flow increases renal oxygen demand
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complications of low-dosedopamine
Increase arrhythmias
Increased myocardial oxygen demand
Gut ischemia
Suppressed respiratory drive
Increased sensitivity to radiocontrast agents
Decreases in T-cell activity
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dopamine 2.0: fenoldapam
Isolated DA-1 activity
Licensed as an IV anti-hypertensive
Increases medullary blood flow more thancortical blood flow Improved oxygenation
Does not increase renal work
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RCT of fenoldapam
155 patients randomized within 24 hours of50% increase in Cr
Primary end-point incidence of need-for-dialysis and/or survival at 21 days
Fenoldapam or half normal saline for 72hours
Protocolized definition of need-for-dialysis
Tumlin JA, Finkel KW, Murray PT, Et al. Am J Kidney Dis. 2005; 46:26-34.
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P=0.235 P=0.163 P=0.068
P=0.048 P=0.015P=0.036 P=0.022
Tumlin JA, Finkel KW, Murray PT, Et al. Am J Kidney Dis. 2005; 46:26-34.
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Tumlin JA, Finkel KW, Murray PT, Et al. Am J Kidney Dis. 2005; 46:26-34.
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prophylactic fenoldapam in sepsis
300 patients with sepsis and no signs of AKI Non-oliguric
Cr < 1.7
Randomized to prophylactic fenoldapam vsplacebo
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P=0.006
P=0.056
Fenoldapam
Placebo
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atrial natriuretic peptide
Recombinant Anaritide is therapeutic form
Dilates afferent arterioles
Improves GFR and urine output in animalmodels of ATN
Three high profile studies looked at usingANP in human AKI.
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radiocontrast nephropathy
30 minutes of ANPbefore contrast
30 minutes of ANP aftercontrast
Cr > 1.8
Randomized to placeboor 1 of 3 doses ofanaritide
Creatinine increase of0.5 or 25% defined RCN
Kurnik B, Allgren RL, Genter FC. Am J Kid Dis 1998; 31: 674-80.
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Allgren R, Manbury T, Rahman SN. N Eng J Med 1997; 336: 828-34.
504 critically ill patients
Creatinine at randomizationwas 4.6
75% had a normal BLcreatinine
24-hour infusion of Anaritide
p=0.008
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Lewis J, Salem M, Chertow G. Am J Kid Dis 2000; 36: 767-74.
oliguric follow-up. strict EBM.
222 oliguric patients 24-hour infusion of ANP
P=0.22
P=0.51 P<0.001
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fixing everything that was wrong
Early treatment 50% increase in creatinine
Low dose anaritide 50 ng/kg/min vs 200 ng/kg/min
Anaritide run continuously until renal recovery ordialysis. Previous studies used 24 hour infusion
Protocol defined indication for dialysis UO < 0.5 cc/kg/hr
for 3 hours
Cr > 4.5
Pulmonary edema andFiO2 >0.8
K>6.0
Swärd K, Valsson F, Odencrants P, Et al. Crit Care Med 2004; 32: 1310-5.
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N=61
Average Cr 2.3
Swärd K, Valsson F, Odencrants P, Et al. Crit Care Med 2004; 32: 1310-5.
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summary
Prognosis is grim
We now have a validated, consensus definition R isk
I njury
F ailure
L oss of function
E srd
Outpatient and inpatient acquired ARF differ inetiology
Hospital acquired disease is your fault
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summary
FE of Urea is a validated way to separate pre-renalfrom AKI even in the presence of diuretics
Use of high dose dialysis regardless of methodologyoffers a survival benefit
There is no proven benefit of one modality overanother Except peritoneal dialysis which has been proven to be
inferior to CVVH
Dopamine doesn’t work
Fenoldapam and anaritide may have a role inreducing mortality from ARF.
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Done