Download - Acute Renal Failure Lecture
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acute renal failure…from basics to the latest advances
Joel M. Topf, MDClinical Nephrologist
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the housemoment
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Dr. Haas invented the first dialysis machine designed for humans and in 1928 he treated 6 patients. All of them died.
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In 1943, Willem Kolff’s, working in the Nazi occupied Netherlands created the second human dialysis machine.
In 1943 he dialyzed his first patient, a young man with acute nephritis.
In 1945, a 67-year-old woman in uremic coma presented to Dr Kolff.
Dr. Haas
Regained consciousness after 11 hours of hemodialysis.
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01020304050607080
Mortality (%)
Sepsis Other Causes
Mortality by Etiology
Commonly quoted mortality of 70% is for dialysis requiring ICU patients
For hospital acquired ARF: 20%
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37 year old AA femaleMultiple GSWProlonged
hypotensionAorta was cross
clamped during exploratory laparotomy
Anuric x 18 hoursCr from 0.8 to 2.2
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36 y.o. African American women with menorrhagia.
Has prolonged bleeding following fibroidectomy
Contrasted CT scan used to determine source of bleeding.
Cr rises from 0.8 to 2.2Patient 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 nephropathy ARF is defined by a
0.5 mg/dL or 25% increase in serum
creatinine
biochemical definitions
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Dialysis dependent ARF is often used in retrospective cohorts Easy to capture Unambiguous Important end-
point
event drivendefinitions
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R iskI njuryF ailureL oss of functionE nd-Stage Renal disease
rifle criteria for stratifying 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 or
anuria 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 4 weeks.
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 3 months.
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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 consecutive
admissions to a university hospital Excluded kids Kidney transplant and
dialysis patients Patients admitted for
< 24 hoursUsing RIFLE:
Risk 9.1% Injury 5.2% Failure 3.7%
Risk9%
No Renal failure82%
Failure4%
Injury5%
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
Pittsburgh has 7 ICUs5,383 patients
Excluded dialysis Subsequent admissions
Frequency of acute Kidney failure: No AKD 1,766 Risk 670 Injury 1,436 Failure 1,511
No Renal failure33%
Risk12%
Failure28%
Injury27%
Hoste E, Clermont G, Kersten A. Crit Care 2006 Vol 310
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0
5
10
15
20
25
30
No AKI Risk Injury Failure
MortalityRRTLOSICU LOS
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RIFLE is dependent on creatinine.creatine is a functional marker of organ damage
Functional markers: old and busted
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biomarkers are foot prints of actual organ damage
Biomarkers, new hotness
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functional versus biomarkers
Functional Marker Biomarker
Liver damage HypoalbuminemiaCoagulopathy
SGOTSGPTGGT
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functional versus biomarkers
Functional Marker Biomarker
Liver damage HypoalbuminemiaCoagulopathy
SGOTSGPTGGT
Heart damage HypotensionArrhythmia
Troponin ITroponin TCK-MB
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functional versus biomarkers
Functional Marker Biomarker
Liver damage HypoalbuminemiaCoagulopathy
SGOTSGPTGGT
Heart damage HypotensionArrhythmia
Troponin ITroponin TCK-MB
Kidney damageCreatinineBUNCystatin C
KIM-1NGAL
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creatinine as a lagging indicator4,118 Cardiac surgery patientsProspectively looked at changes of
creatinine 48 hours post-op on 30-day mortality
All odds ratios were controlled for 26 variables found to be significant predictors of mortality 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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Transmembrane protein expressed in the proximal tubule.
Expression is increased following ischemic damage
Can be found 12 hours after renal insult
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)Transmembrane
protein expressed in the proximal tubule.
Expression is inc-reased following ischemic damage
Can be found 12 hours after renal insult
Time starts at aorta cross clamp. 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 secreted by the kidney in res-ponse to ischemic injury
Early data in children showed nearly perfect sensitivity and specificity
False positives with UTI
Prospective observational trial
81 adults going for Cardiac surgery 65 No AKI
1 died of MOF 16 AKI (Risk or
higher)5 required CVVH5 died of MOF
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differential diagnosis
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etiologies of arfSeventy 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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Community acquired49.7%
Hospital acquired50.3%
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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56
21717
48
29
1112
39
30
2011
0%
20%
40%
60%
80%
100%
< 65 65-79 > 79Ages
otherPost RenalPre RenalRenal
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
Medication16%
Contrast11%
Post-Op15%
Hypotension11%
Obstruction2% Other
7%Unknown
3%CHF4%
Other2%
Sepsis7%Volume
Contraction22%
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hospital acquired acute renal failure
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Pre-renal azotemiaNo BP, no pee pee
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differentiation of prerenal from intrinsic renal diseaseUse of FENa
Fraction of filtered sodium which is excreted in the urine.
Patients with prerenal azotemia will be sodium avid and minimize renal excretion of sodium lowering the FENa below 1%
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Sr Na
Ur Na Ur Cr
Sr CrSr NaSr Cr x Ur
Nax Ur Cr
FENa =
FENa the easy wayFENa is a small number 0.1% to 3% So the calculation will be 0.001-0.03 prior to
converting to percent by X 100So make the fraction small by putting the
small numbers over the big numbers
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FeNa. what is it good for? The discriminator for differentiating between prerenal
azotemia and ATN is 1%:
FENa < 1 indicates pre-renal azotemia
Sensitivity: 90% Specificity: 93%
FENa > 1 indicates ATN
Sensitivity: 93% Specificity: 90%
Pre-renal azotemia
ATN (oliguric and non-oliguric)
FENa < 1 27 4
FENa > 1 3 51
Pre-renal azotemia
ATN (oliguric and non-oliguric)
FENa > 1 3 51
FENa < 1 27 4
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 Hemoglobinuric
nephropathy Myoglobinuric
nephropathy Acute rejection Cyclosporin and
Tacrolimus toxicity* Hepatorenal syndrome Acute interstitial
nephritis
ATN tested too early ATN with CHF ATN with cirrhosis ATN with severe burns Non-oliguric acute renal
failure Acute
Glomerulonephritis ACEi in bilateral RAS or
in RAS with solitary kidney
NSAID induced ARF
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FeNa false negativesDiuretics Metabolic alkalosis
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Kaplan, Kohn. American J Nephrol, 1992; 12: 49-54.
fractional excretion of ureaBased on the physiologic increase in
urea reabsorption with pre-renal azotemia
Normal FE Urea is 50-65% in well hydrated individuals
In prerenal azotemia this falls below 35%
Not affected by diureticsSr NaSr Cr x Ur
Nax Ur Cr
FENa =Sr UreaSr Cr x Ur
Ureax Ur Cr
FEurea =
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Carvounis, Sabeeha, Nisar, Et al. Kidney Int, 2002 Vol 62. p 2223-2229
FEurea in the differential diagnosis of atn102 patients with ARFGold standard was consultants full
analysis and retrospective analysis of response to treatment.
Divided the cases into: ATN Prerenal without diuretic Prerenal treated with diuretics
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92 91
50
90
0
20
40
60
80
100
Sensitivity (%)
Pre-Renal, Nodiuretics
Pre-Renal, Diuretics
FENaFEUrea
FENa
FEUrea
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therapyRenal replacement therapyFurosemideDopamineFenoldapamhANP (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
rviv
al
Severity of illness (CCARF Score)
High dose
Low dose
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Ronco’s landmark dialysis dose study425 patients with dialysis dependent
acute renal failure were randomized to one of three doses 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 three days/wk dialysis160 patients
Schiffl, H. et al. N Engl J Med 2002;346:305-310
46
28
0102030405060708090
100
Frequency (%)
3 days/week HD Daily HD
Hospital mortality16
9
02468
10121416
Days
3 days/week HD Daily HD
Duration of ARF
P=0.01 P=0.001
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Schiffl, H. et al. N Engl J Med 2002;346:305-310
1.06
3.02 3.273.92
0.00.51.01.52.02.53.03.54.0
Odds Ratio
Apache IIIscore
Oliguria Sepsis Alternate-day HD
P=0.002
P=0.005P=0.007
P=0.02
odds ratio of death
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adding dialysis to CVVH206 dialysis patients randomized to
CVVH 1-2.5 L/hr CVVH plus 1-1.5 liters of dialysate
(CVVHDF)
39
59
0
10
20
30
40
50
60
Fraction (%)
CVVH CVVHDF
28-day survival
34
59
0
10
20
30
40
50
60
Fraction (%)
CVVH CVVHDF
90-day survival
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 in Bouman. 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 dataUS trial: ATN
Primarily veterans hospital Prospective randomized, multi-center trial Dose finding study
Conventional daily dialysisSLEDCVVHCVVHDCVVHDF
Australian trial: RENAL
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furosemideDecreased activity of the ascending
loop of Henle decreases renal oxygen demand by the kidney 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 of ICU patients
Diuretic responsiveness determined survival
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furosemide the rct338 with dialysis dependent ARFRandomized to high dose furosemide
(2,000 mg/day) vs placeboEnd-point length of dialysisNo improvement of survival, length of
dialysis, number of dialysis sessionsShorter 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
low dose dopamine increases renal blood flow and induces diuresis
Patients in the intensive care unit do not respond this way.
Increased RBF
Increased urine
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dopamine: still doesn’t work In healthy volunteers
low dose dopamine increases renal blood flow and induces diuresis
Patients in the intensive care unit do not respond this 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
low dose dopamine increases renal blood flow and induces diuresis
Patients in the intensive care unit do not respond this way. RCT of 380 ICU patients
with early renal failure Meta-analysis of 58
studies and 2,149 patientsANZICS Clinical Trials Group. Lancet 2000;356:2139-47.
Kellum JA, Decker JM.Crit Care 2001; 29:1526-31.
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Dopamine increases cortical blood flow more than medullary blood flow Cortical blood flow increases GFR Cortical blood flow increases renal oxygen
demand
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dopamine 2.0: fenoldapamIsolated DA-1 activityLicensed as an IV anti-hypertensiveIncreases medullary blood flow more
than cortical blood flow Improved oxygenation Does not increase renal work
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RCT of fenoldapam155 patients randomized within 24
hours of 50% increase in CrPrimary end-point incidence of need-
for-dialysis and/or survival at 21 daysFenoldapam or half normal saline for
72 hoursProtocolized 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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27.5
38.7
16.25
25.3
13.8
25.3
05
10152025303540
Frequency (%)
Dialysis or Death Dialysis Death
FenoldapamPlacebo
25.9
44.2
13
32.7
05
1015202530354045
Frequency (%)
Dialysis or Death Dialysis
Non-Diabetics
17.6
38.9
8.8
38.9
05
10152025303540
Frequency (%)
Dialysis or Death Dialysis
Cardiac Surgery
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 sepsis300 patients with sepsis and no signs of
AKI Non-oliguric Cr < 1.7
Randomized to prophylactic fenoldapam vs placebo
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19.3
34
6.6
14
05
101520253035
Frequency (%)
Cr > 1.7 Cr > 3.5
Fenoldapam Placebo
P=0.006
P=0.056
Fenoldapam
Placebo
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atrial natriuretic peptideRecombinant Anaritide is therapeutic
formDilates afferent arteriolesImproves GFR and urine output in
animal models of ATNThree high profile studies looked at
using ANP in human AKI.
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radiocontrast nephropathy30 minutes of ANP
before contrast30 minutes of ANP
after contrastCr > 1.8Randomized to
placebo or 1 of 3 doses of anaritide
Creatinine increase of 0.5 or 25% defined RCN
Kurnik B, Allgren RL, Genter FC. Am J Kid Dis 1998; 31: 674-80.
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4743
05
101520253035404550
Dialysis-free Survival (%)
Placebo Anaritide
Allgren R, Manbury T, Rahman SN. N Eng J Med 1997; 336: 828-34.
05
101520253035404550
Hypotension (%)
Placebo Anaritide
504 critically ill patients Creatinine at
randomization was 4.6
75% had a normal BL creatinine
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
58
97
0102030405060708090
100
Frequency (%)
Placebo Anaritide
SBP < 90 mmHg
15 21
0102030405060708090
100
Frequency (%)
Placebo Anaritide
21 day dialysis free survival
56 60
0102030405060708090
100
Frequency (%)
Placebo Anaritide
60 day mortality
P=0.22
P=0.51 P<0.001
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fixing everything that was wrongEarly treatment
50% increase in creatinineLow dose anaritide
50 ng/kg/min vs 200 ng/kg/minAnaritide run continuously until renal
recovery or dialysis. 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 and FiO2 >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=61Average Cr 2.3
5259
0102030405060708090
100
Hypotension (%)
Placebo Anaritide
Swärd K, Valsson F, Odencrants P, Et al. Crit Care Med 2004; 32: 1310-5.
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summaryPrognosis is grimWe now have a validated, consensus definition
R isk I njury F ailure L oss of function E srd
Outpatient and inpatient acquired ARF differ in etiology
Hospital acquired disease is your fault
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summaryFE of Urea is a validated way to separate pre-
renal from AKI even in the presence of diureticsUse of high dose dialysis regardless of
methodology offers a survival benefitThere is no proven benefit of one modality over
another Except peritoneal dialysis which has been proven to
be inferior to CVVHDopamine doesn’t workFenoldapam and anaritide may have a role in
reducing mortality from ARF.
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Done