AKI Lecture 2010

acute renal failure … from basics to the latest advances Joel M. Topf, MD Clinical Nephrologist http://pbfluids.com

the house moment

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.                 Regained consciousness after 11 hours of hemodialysis.       Dr. Haas

Commonly quoted mortality of 70% is for dialysis requiring ICU patients
For hospital acquired ARF: 20%

37 year old AA female
Multiple GSW
Prolonged hypotension
Aorta was cross clamped during exploratory laparotomy
Anuric x 18 hours
Cr 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 2.2
Patient 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 driven definitions

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

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

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.

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
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%
Uchino S, Bellomo R, Goldsmith D. Crit Care Med 2006 Vol 34 1913-1917.

Hospital Mortality >3x BL Cr Cr > 4

nice criteria. do they work in the icu?
University of Pittsburgh has 7 ICUs
5,383 patients
Excluded dialysis
Subsequent admissions
Frequency of acute Kidney failure:
No AKD 1,766
Risk 670
Injury 1,436
Failure 1,511
Hoste E, Clermont G, Kersten A. Crit Care 2006 Vol 310

when Hoste looked at markers of severity of illness excluding the renal system: No survival difference between the 4 groups: • Lack of renal failure • Risk • Injury • Failure

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 damage Hypoalbuminemia Coagulopathy SGOT SGPT GGT

functional versus biomarkers Functional Marker Biomarker Liver damage Hypoalbuminemia Coagulopathy SGOT SGPT GGT Heart damage Hypotension Arrhythmia Troponin I Troponin T CK-MB

functional versus biomarkers Functional Marker Biomarker Liver damage Hypoalbuminemia Coagulopathy SGOT SGPT GGT Heart damage Hypotension Arrhythmia Troponin I Troponin T CK-MB Kidney damage Creatinine BUN Cystatin C KIM-1 NGAL

creatinine as a lagging indicator
4,118 Cardiac surgery patients
Prospectively 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
candidates for a renal troponin: kidney injury molecule-1 (kim-1) 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)
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.

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 CVVH
5 died of MOF
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.

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

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.

N=103 N=256 N=389 Pascual J, Liano F. J Am Geriatr Soc 1998, 46: 1-5.

hospital acquired acute renal failure

Pre-renal azotemia No BP, no pee pee

Pre-renal ARF
Properly functioning kidney, properly responding to a drop in systemic and renal perfusion
no bp, no pee pee RPF a u t o r e g u l a t i o n GFR

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 Na Filtered Na Fractional excretion of sodium:

Excreted Na = Urine Na x Urine Volume Calculating the Numerator

Filtered Na = Serum Na x GFR Calculating the Denominator GFR = Urine Cr x Urine Volume Serum Cr Filtered Na = Serum Na x UrCr x UrVol Serum Cr

Urine Na x Urine Volume Serum Na x UrCr x Urine Volume Serum Cr FENa = Excreted Na Filtered Na FENa = Urine Na Serum Na x UrCr Serum Cr FENa = Urine Na x Serum Cr Serum Na x UrCr 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 100
So make the fraction small by putting the small numbers over the big numbers
Sr Na
Ur Na
Ur Cr
Sr Cr
Sr Na Sr Cr x Ur Na x Ur Cr FENa =

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%
Miller, Schrier, Et al. Annals Int Med, 1978 Vol 89. p 47-50 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

Low 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 Positive

FeNa false negatives
Diuretics
Metabolic alkalosis
High FENa, but pre-renal

Patients with a decreased FENa were tested earlier 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 a subsequent FENa > 1%
Low fractional excretion of sodium in acute renal failure Role of timing of the test and ischemia

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 diuretics
Kaplan, Kohn. American J Nephrol, 1992; 12: 49-54. Sr Na Sr Cr x Ur Na x Ur Cr FENa = Sr Urea Sr Cr x Ur Urea x Ur Cr FEurea =

FEurea in the differential diagnosis of atn
102 patients with ARF
Gold standard was consultants full analysis and retrospective analysis of response to treatment.
Divided the cases into:
ATN
Prerenal without diuretic
Prerenal treated with diuretics
Carvounis, Sabeeha, Nisar, Et al. Kidney Int, 2002 Vol 62. p 2223-2229

FENa FEUrea

therapy Renal replacement therapy Furosemide Dopamine Fenoldapam hANP (Anaritide)

renal replacement therapy

Dialysate Conventional Dialysis Diffusive Clearance 136 5.8 108 17 67 3.8 145 2 110 35 0 0

80 mmol K 5.8 mmol/L = 13.8 liters Isolated Ultrafiltration: CHF Solutions Minimal clearance 136 5.8 108 17 67 3.8 136 5.8 108 17 67 3.8

Ultrafilter 3+ liters/hour Replace all ultrafiltrate with sterile fluid at ideal plasma concentrations CVVH Convective clearance 136 5.8 108 17 67 3.8 140 2 108 30 0 0 140 4 108 30 0 0

Post-filter replacement fluid CVVH Convective clearance

Pre-filter replacement fluid CVVH Convective clearance

CVVHDF Convective and Diffusive

high dose dialysis survival 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/hr 35 mL/kg/hr 45 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 P=0.01 P=0.001

odds ratio of death Schiffl, H. et al. N Engl J Med 2002;346:305-310 P=0.002 P=0.005 P=0.007 P=0.02

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.

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 10 Odds 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 trial
Prospective 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 care 561 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 out
ICU 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
Retrospective review of ICU patients
Diuretic responsiveness determined survival
Mehta, R. L. et al. JAMA 2002;288:2547-2553.

furosemide the rct
338 with dialysis dependent ARF
Randomized to high dose furosemide (2,000 mg/day) vs placebo
End-point length of dialysis
No improvement of survival, length of dialysis, 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.

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

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.

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: the randomized controlled 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 renal disease
A rise in serum Cr of 0.9 mg/dL in less than 24 hours
The primary outcome was peak serum creatinine
ANZICS Clinical Trials Group. Lancet 2000;356:2139-47.

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

meta-analysis
Kellum and Decker searched MedLine (English and non-English literature) for every article on human trials with dopamine for the treatment or prevention of ARF from 1966 to 1999.
They included 58 studies with 2149 patients
Kellum JA, Decker JM.Crit Care 2001; 29:1526-31.

Exclude radiocontrast studies
Limited to heart studies
Excludes studies in which had abnormal control groups or increased variance

Dopamine increases cortical blood flow more than medullary blood flow
Cortical blood flow increases GFR
Cortical blood flow increases renal oxygen demand

complications of low-dose dopamine
Increase arrhythmias
Increased myocardial oxygen demand
Gut ischemia
Suppressed respiratory drive
Increased sensitivity to radiocontrast agents
Decreases in T-cell activity

dopamine 2.0: fenoldapam
Isolated DA-1 activity
Licensed as an IV anti-hypertensive
Increases 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.

P=0.235 P=0.163 P=0.068 P=0.048 P=0.015 P=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.

P=0.006 P=0.056 Fenoldapam Placebo

atrial natriuretic peptide
Recombinant Anaritide is therapeutic form
Dilates afferent arterioles
Improves GFR and urine output in animal models of ATN
Three 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 > 1.8
Randomized 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.

504 critically ill patients
Creatinine at randomization was 4.6
75% had a normal BL creatinine
24-hour infusion of Anaritide
Allgren R, Manbury T, Rahman SN. N Eng J Med 1997; 336: 828-34. p =0.008

oliguric follow-up. strict EBM.
222 oliguric patients
24-hour infusion of ANP
Lewis J, Salem M, Chertow G. Am J Kid Dis 2000; 36: 767-74. 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=61
Average Cr 2.3
Swärd K, Valsson F, Odencrants P, Et al. Crit Care Med 2004; 32: 1310-5.

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 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 patient
Dopamine doesn’t work
Fenoldapam and anaritide may have a role in reducing mortality from ARF.

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AKI Lecture 2010

by Joel Topf on Jul 08, 2010

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