Acute Renal Failure Lecture

acute renal failure…from basics to the latest advances

Joel M. Topf, MDClinical Nephrologist

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 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.

01020304050607080

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 iskI njuryF ailureL oss of functionE 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.





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.




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 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.

>3x

BL

Cr

Cr >

4

Hos

pita

l Mor

talit

y

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 damage HypoalbuminemiaCoagulopathy

SGOTSGPTGGT




SGOTSGPTGGT

Heart damage HypotensionArrhythmia

Troponin ITroponin TCK-MB




SGOTSGPTGGT

Heart damage HypotensionArrhythmia

Troponin ITroponin TCK-MB

Kidney damageCreatinineBUNCystatin C

KIM-1NGAL

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

<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 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

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

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.

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 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%

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

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 negativesDiuretics Metabolic alkalosis

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 =

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

92 91

50

90

0

20

40

60

80

100

Sensitivity (%)

Pre-Renal, Nodiuretics

Pre-Renal, Diuretics

FENaFEUrea

FENa

FEUrea

therapyRenal 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


Pre-filter replacement fluid


CVVHDFConvective and Diffusive

high dose dialysissu

rviv

al

Severity of illness (CCARF Score)

High dose

Low dose

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

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 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

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

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.

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.

future dataUS trial: ATN

Primarily veterans hospital Prospective randomized, multi-center trial Dose finding study

Conventional daily dialysisSLEDCVVHCVVHDCVVHDF

Australian trial: RENAL

furosemideDecreased 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 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.

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



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.



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.

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: fenoldapamIsolated 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 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.

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


prophylactic fenoldapam in sepsis300 patients with sepsis and no signs of

AKI Non-oliguric Cr < 1.7

Randomized to prophylactic fenoldapam vs placebo

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

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.

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.

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

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

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.

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.

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

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.

Acute Renal Failure Lecture

Health & Medicine

Transcript of Acute Renal Failure Lecture