Post on 07-May-2015
acute renal failure…from basics to the latest advances
Joel M. Topf, MDClinical Nephrologist
http://pbfluids.com
the housemoment
Dr. Haas invented the first dialysis machine designed for humans and in 1928 he treated 6 patients.
All of them died.
In 1943, Willem Kolff’s, working in 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 Dr. Haas
Regained consciousness after 11 hours of hemodialysis.
0
10
20
30
40
50
60
70
80
Mortality (%)
Sepsis Other Causes
Mortality by Etiology
Commonly quoted mortality of 70% is for dialysis requiring ICU patients
For hospital acquired ARF: 20%
37 year old AA femaleMultiple GSWProlonged
hypotensionAorta was cross
clamped during exploratory laparotomy
Anuric x 18 hoursCr from 0.8 to 2.2
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
Same rise in creatinine.
Same diagnosis: acute renal failure.
Two completely different diseases.
Two women.
Same age.
Same race.
definition of acute renal failure
“Acute and sustained reduction in renal function.”
35
definitions
Contrast nephropathy ARF is defined by a
0.5 mg/dL or 25% increase in serum
creatinine
biochemical definitions
Dialysis dependent ARF is often used in retrospective cohorts Easy to capture Unambiguous Important end-
point
event drivendefinitions
R isk
I njury
F ailure
L oss of function
E nd-Stage Renal disease
rifle criteria for stratifying arf
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
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
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
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
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.
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
nice criteria. do they work?
20,126 consecutive admissions to a university hospital Excluded kids Kidney transplant and
dialysis patients Patients admitted for
< 24 hours
Using 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.
>3x
BL
Cr
Cr
> 4
Ho
spita
l Mo
rtal
ity
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
0
5
10
15
20
25
30
No AKI Risk Injury Failure
MortalityRRTLOSICU LOS
RIFLE is dependent on creatinine.creatine is a functional marker of organ damage
Functional markers: old and busted
biomarkers are foot prints of actual organ damage
Biomarkers, new hotness
functional versus biomarkers
Functional Marker Biomarker
Liver damageHypoalbuminemiaCoagulopathy
SGOTSGPTGGT
functional versus biomarkers
Functional Marker Biomarker
Liver damageHypoalbuminemiaCoagulopathy
SGOTSGPTGGT
Heart damageHypotensionArrhythmia
Troponin ITroponin TCK-MB
functional versus biomarkers
Functional Marker Biomarker
Liver damageHypoalbuminemiaCoagulopathy
SGOTSGPTGGT
Heart damageHypotensionArrhythmia
Troponin ITroponin TCK-MB
Kidney damageCreatinineBUNCystatin C
KIM-1NGAL
creatinine as a lagging indicator
4,118 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
<0.5 0.4 0.2 0.1 0.3 0.5 0.7 0.9
Creatinine falls Creatinine rises
Delta Creatinine (mg/dL)
candidates for a renal troponin:
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)
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.
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
differential diagnosis
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
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.
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.
56
21
717
48
29
1112
39
30
20
11
0%
20%
40%
60%
80%
100%
< 65 65-79 > 79
Ages
otherPost RenalPre RenalRenal
N=103N=256N=389
Pascual J, Liano F. J Am Geriatr Soc 1998, 46: 1-5.
hospital acquired acute renal failure
Medication16%
Contrast11%
Post-Op15%
Hypotension11%
Obstruction2% Other
7%Unknown
3%
CHF4%
Other2%
Sepsis7%Volume
Contraction22%
hospital acquired acute renal failure
Pre-renal azotemiaNo BP, no pee pee
differentiation of prerenal from intrinsic renal disease
Use 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
Excreted NaFiltered Na
Fractional excretion of sodium:
Excreted Na = Urine Na x Urine Volume
Calculating the Numerator
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
Excreted NaFiltered Na
FENa =
Urine Na x Urine VolumeSerum Na x UrCr x Urine
VolumeSerum Cr
FENa =
Urine NaSerum Na x UrCr Serum Cr
FENa =
Urine Na x Serum CrSerum Na x UrCr
FENa =
Sr Na
Ur Na Ur Cr
Sr Cr
Sr Na
Sr Cr x Ur Nax Ur Cr
FENa =
FENa the easy way
FENa 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
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
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
FeNa false negatives
Diuretics Metabolic alkalosis
High FENa, but pre-renal
Kaplan, Kohn. American J Nephrol, 1992; 12: 49-54.
fractional excretion of urea
Based 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 Na
Sr Cr x Ur Nax Ur Cr
FENa =Sr Urea
Sr Cr x Ur Urea
x Ur CrFEurea =
Carvounis, Sabeeha, Nisar, Et al. Kidney Int, 2002 Vol 62. p 2223-2229
FEurea in the differential diagnosis of atn
102 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
92 91
50
90
0
20
40
60
80
100
Sensitivity (%)
Pre-Renal, Nodiuretics
Pre-Renal, Diuretics
FENaFEUrea
FENa
FEUrea
therapy
Renal replacement therapyFurosemideDopamineFenoldapamhANP (Anaritide)
renal replacement therapy
Dialysate
1365.8
10817
67
3.8
1452
11035
0
0
Conventional DialysisDiffusive Clearance
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
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
Post-filter replacement fluid
CVVHConvective clearance
Pre-filter replacement fluid
CVVHConvective clearance
CVVHDFConvective and Diffusive
high dose dialysissu
rviv
al
Severity of illness (CCARF Score)
High dose
Low dose
Ronco’s landmark dialysis dose study
425 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
20 mL/kg/hr20 mL/kg/hr
35 mL/kg/hr35 mL/kg/hr
45 mL/kg/hr45 mL/kg/hr
Ronco C, Bellomo R, Hormea P, Et al. Lancet 2000; 355: 26-30.
Schiffl: daily dialysis versus three days/wk dialysis
160 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 mortality
16
9
0
2
4
6
8
10
12
14
16
Days
3 days/week HD Daily HD
Duration of ARF
P=0.01 P=0.001
Schiffl, H. et al. N Engl J Med 2002;346:305-310
1.06
3.023.27
3.92
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Odds Ratio
Apache IIIscore
Oliguria Sepsis Alternate-day HD
P=0.002
P=0.005P=0.007
P=0.02
odds ratio of death
adding dialysis to CVVH
206 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.
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.
ATN trial
US trialProspective randomized, multi-center trial
27 institutions primarily veterans hospitals
Dose finding study, modality agnostic Conventional dialysis SLED CVVH CVVHD CVVHDF
interventions
endpoint
Primary Endpoint: All-cause mortality at day 60.
Secondary endpoints: In-hospital death Recovery of renal function (CrCl>20)
defined as complete if Cr was <0.5 over the baseline
Duration of renal replacement therapy Dialysis free at 60 days Duration of ICU stay Return to previous home at day 60
results
563 enrolled in standard care561 randomized to intensive therapy
60% sepsis
80% vented
Apache II score 26 (predicted mortality 55%)
BUN at initiation of RRT 65
Roughly half in the MICU and half in the SICU
This report currently should be
viewed as the definitive study defining dialysis dosing in critically ill patients with AKI
H. David Hume
…the patient dies from multi-organ failure while in exquisite
electrolyte & fluid balance.
Fluid balance?
Patients stratified by net fluid gain from admission to initiation of CRT
Fluid in – fluid outICU admit weight X 100
longer ICU stay
higher mortality
more multi-organ dysfunction
more likely to be intubated
more inotropes
more sepsis
higher PRISM score
More fluid. More sick.
Worse fluid overload severity remained independently associated with mortality (OR, 1.03; 95% CI, 1.01-1.05). The relationship was satisfactorily linear and the OR
suggests a 3% increase in mortality for each 1% increase in degree of fluid overload at CRRT initiation.
80 kg adult
Is and Os: 2,400 mL in (100 mL/hr) and 1,600 mL of urine (67 mL/hr)
Positive balance of 800 mL. If after 3 days and the patient becomes oliguric with only 400 mL of urine output for two days (2,000 mL positive per day) before initiating CRT.
That patient would be up 6,400 mL or 8% of bodyweight
24% increase in mortality compared to someone with matched ins and outs
[in regards to the kidney] these excretory operations are incidental to the major task of keeping our internal
environments in the ideal, balanced state.Homer Smith from Fish to Philosopher
Medical therapy of acute kidney injury
Today Loop diuretics dopamine
Tomorrow Fenoldapam ANP
furosemide
Decreased activity of the ascending loop of Henle decreases renal oxygen demand by the kidney Better align demand and supply in ischemia
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
furosemide the rct
338 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.
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
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.
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 patients ANZICS Clinical Trials Group. Lancet 2000;356:2139-47.
Kellum JA, Decker JM.Crit Care 2001; 29:1526-31.
Dopamine increases cortical blood flow more than medullary blood flow Cortical blood flow increases GFR Cortical blood flow increases renal oxygen
demand
dopamine 2.0: fenoldapam
Isolated DA-1 activityLicensed as an IV anti-hypertensiveIncreases medullary blood flow more
than cortical blood flow Improved oxygenation Does not increase renal work
RCT of fenoldapam
155 patients randomized within 24 hours of 50% increase in Cr
Primary end-point incidence of need-for-dialysis and/or survival at 21 days
Fenoldapam or half normal saline for 72 hours
Protocolized definition of need-for-dialysis
Tumlin JA, Finkel KW, Murray PT, Et al. Am J Kidney Dis. 2005; 46:26-34.
27.5
38.7
16.25
25.3
13.8
25.3
0
5
10
15
20
25
30
35
40
Frequency (%)
Dialysis or Death Dialysis Death
FenoldapamPlacebo
25.9
44.2
13
32.7
05
101520
2530354045
Frequency (%)
Dialysis or Death Dialysis
Non-Diabetics
17.6
38.9
8.8
38.9
0
5
10
15
20
25
30
35
40
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.
Tumlin JA, Finkel KW, Murray PT, Et al. Am J Kidney Dis. 2005; 46:26-34.
prophylactic fenoldapam in sepsis
300 patients with sepsis and no signs of AKI Non-oliguric Cr < 1.7
Randomized to prophylactic fenoldapam vs placebo
Prophylaxis is a way to get around the problem of late diagnosis due to the lack of an established biomarker.
19.3
34
6.6
14
0
5
10
15
20
25
30
35
Frequency (%)
Cr > 1.7 Cr > 3.5
Fenoldapam Placebo
P=0.006
P=0.056
Fenoldapam
Placebo
atrial natriuretic peptide
Recombinant Anaritide is therapeutic form
Dilates afferent arteriolesImproves GFR and urine output in
animal models of ATNThree high profile studies looked at
using ANP in human AKI.
radiocontrast nephropathy
30 minutes of ANP before contrast
30 minutes of ANP after contrast
Cr > 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.
4743
0
5
10
15
20
25
30
35
40
45
50
Dialysis-free Survival (%)
Placebo Anaritide
Allgren R, Manbury T, Rahman SN. N Eng J Med 1997; 336: 828-34.
0
5
10
15
20
25
30
35
40
45
50
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
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
1521
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
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 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.
N=61Average Cr 2.3
5259
010
2030
4050
6070
8090
100
Hypotension (%)
Placebo Anaritide
Swärd K, Valsson F, Odencrants P, Et al. Crit Care Med 2004; 32: 1310-5.
summary
Prognosis 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
summary
FE of Urea is a validated way to separate pre-renal from AKI even in the presence of diuretics
Use of high dose dialysis regardless of methodology offers no survival benefit
Do not fluid overload your patientDopamine doesn’t workFenoldapam and anaritide may have a role in
reducing mortality from ARF.
Done