AKI Lecture 2010

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


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



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



hrs


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.



hrs


hrs



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.


hrs


hrs



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




SGOTSGPTGGT

Heart damageHypotensionArrhythmia

Troponin ITroponin TCK-MB




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.

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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

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40

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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


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 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



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

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28

0102030405060708090

100

Frequency (%)

3 days/week HD Daily HD

Hospital mortality

16

9

0

2

4

6

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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

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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



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 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


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.

AKI Lecture 2010

Education

Transcript of AKI Lecture 2010