ARF No ATN Data

acute renal failure…from basics to the latest advances

Joel M. Topf, MD

Clinical Nephrologist

the housemoment

Dr. Haas invented the first dialysis machine designedfor humans and in 1928 he treated 6 patients.

All of them died.

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.

Commonly quotedmortality of 70% isfor dialysis requiringICU patients

For hospital acquiredARF: 20%

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

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

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 nephropathyARF is defined by a 0.5mg/dL or 25% increase

in serum creatinine

biochemicaldefinitions

Dialysis dependentARF is often used inretrospective 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 forstratifying 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


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 oranuria 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 4weeks.






L oss of function: Need for dialysis for more than 4 weeks


persistent renal failure (i.e. need for dialysis) for more than 3months.





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 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.

>3x

BL

Cr

Cr >

4

Hos

pita

l Mor

talit

y

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

when Hoste looked at markers ofseverity of illness excluding the renalsystem:

No survival difference between the4 groups:

• Lack of renal failure• Risk• Injury• Failure

RIFLE is dependent on creatinine.creatine is a functional marker oforgan damage

Functionalmarkers: oldand busted

biomarkers are foot prints of actualorgan damage

Biomarkers,new hotness

functional versus biomarkers

SGOT

SGPT

GGT

Hypoalbuminemia

CoagulopathyLiver damage

BiomarkerFunctionalMarker


Troponin I

Troponin T

CK-MB

Hypotension

ArrhythmiaHeart damage

SGOT

SGPT

GGT

Hypoalbuminemia




KIM-1

NGAL

Creatinine

BUN

Cystatin CKidney damage

Troponin I

Troponin T

CK-MB

Hypotension

ArrhythmiaHeart damage

SGOT

SGPT

GGT

Hypoalbuminemia



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

<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:

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)

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.

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

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=103N=256N=389

Pascual J, Liano F. J Am Geriatr Soc 1998, 46: 1-5.

hospital acquired acute renal failure

Pre-renal azotemiaNo BP, no pee pee

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

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%

Excreted NaFiltered Na

Fractional excretion ofsodium:

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 Volume

Serum CrFENa =

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 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

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

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

FeNa false negatives

Diuretics Metabolic alkalosis

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

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 =

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

FENa

FEUrea

therapy

Renal replacement therapy

Furosemide

Dopamine

Fenoldapam

hANP (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


Pre-filter replacement fluid


CVVHDFConvective and Diffusive

high dose dialysissu

rvival

Severity of illness (CCARF Score)

High dose

Low dose

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

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 threedays/wk dialysis

160 patients

Schiffl, H. et al. N Engl J Med 2002;346:305-310

P=0.01 P=0.001

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

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 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.

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

furosemide

Decreased activity of the ascending loop ofHenle decreases renal oxygen demand by thekidney 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 ofICU patients

Diuretic responsivenessdetermined survival

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.

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



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.



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.

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.

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

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

A. Exclude radiocontraststudies

B. Limited to heart studies

C. Excludes studies inwhich had abnormalcontrol groups orincreased variance

Dopamine increases cortical blood flow morethan medullary blood flow Cortical blood flow increases GFR

Cortical blood flow increases renal oxygen demand

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

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

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.

P=0.235 P=0.163 P=0.068

P=0.048 P=0.015P=0.036 P=0.022


prophylactic fenoldapam in sepsis

300 patients with sepsis and no signs of AKI Non-oliguric

Cr < 1.7

Randomized to prophylactic fenoldapam vsplacebo

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 animalmodels of ATN

Three high profile studies looked at usingANP in human AKI.

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.

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

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

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.

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 inetiology

Hospital acquired disease is your fault

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.

ARF No ATN Data

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