Holistic Approach to Treatment Adequacy in AKI Claudio Ronco, MD Department of Nephrology, St....

Holistic Approach to Treatment Adequacy in AKI

Claudio Ronco, MD Department

of Nephrology, St. Bortolo Hospital,

International Renal Research Institute

Vicenza - Italy

During the bombing of London in world war II, Bywaters described cases of acute loss of kidney function in severely injured crush victims. Histological evidence for patchy necrosis of renal tubules at autopsy, suggested him to use the term Acute Tubular Necrosis (ATN) to describe this clinical entity.

AKI: historical notices

ARF mortality approached 100% in World War II (no treatment available). Acute hemodialysis was first used clinically during the Korean War in 1950 to treat military casualties, decreasing ARF mortality to about 50%.


Courtesy of Coll. Dr: Paul Teschan

Fluid resuscitation on the battlefield with the rapid evacuation of the casualties to hospitals by helicopter was optimized further during the Vietnam War. For seriously injured casualties the incidence of ischemic ARF was one in 200 in the Korean War and one in 600 in the Vietnam War. This historical sequence of events suggested that early intervention could prevent the occurrence of ARF, at least in military casualties.


In the last half century, much has been learned about the pathogenesis of ischemic and nephrotoxic ARF in experimental models, but there has been very little improvement in mortality. This may be explained by changing demographics: age and comorbidity of patients with ARF continue to rise, possibly obscuring any increased survival related to improved critical care.

AKI: Changing Pattern

Ward8 %

ICU92 %

Ward85%

ICU15%

Vicenza Database 1995 – 2000 Total number of incident cases = 525

Vicenza Database 1974 – 1979 Total number of incident cases = 48

Mortality 54 % Mortality 53 %

Facts1) RRT is a cornerstone for the therapy of of AKI in the ICU

2) Indications have changed over the years (replacement vs support)

3) Mortality has changed over the years and so did the case mix

4) We still have a number of unresolved issues or controversies

a) Timing for therapy start and stop

b) Correct prescription (Dose and Fluid balance)

c) Modality and Schedule

d) Monitoring and delivery

e) Special treatments for special cases

• No consensus on “When” to initiate RRT

• Early initiation probably improves outcomes (but early means what? Admission? Creatinine? Other?

• RIFLE/AKIN Stage stratification may represent a surrogate of timing (severity)

• There is a rationale for early initiation• There are draw backs for early initiation• An objective algorithm has been proposed for RRT

initiationWe need additional clinical studies!

About timing

Seabra et al AJKD 2008

RCT: RR 0.64 (95% CI, 0.40-1.05)

Cohort: RR 0.72 (95% CI, 0.64-0.82)

Electronic Sniffers and RIFLE Alert

RIFLE Alert

You reached RIFLE class “RISK”Baseline Creatinine = 0.9

Actual creatinine = 1.55 x Baseline

Confirm

Variable Thresholds Single AUCs Points added

Mean arterial pressure Lowest on first day of ICU <= 65 mmHg 0.61 1

Temperature Highest on first day of ICU >= 38.2 °C 0.57 2

HCO3 Lowest on first day of ICU <= 23 mmol/L 0.60 1

Urinary output * Lowest on first day of ICU <= 40 ml/h 0.60 1

SOFA Renal * On first day of ICU >= 2 0.73 2

Invasive Mechanical Ventilation On first day of ICU No MV 0.52 1.5

Change of SCr. during ICU stay (mg/dl) * (HS-Adm) >= 0.30 mg/dl 0.63 1.5

Fluid Accumulation * >= 10 % 0.47 1

IRRIV Score

To predict RRT and define late Initiation>= 3.5 pt. including one renal dysfunction markers (*)

0.81 Total: 0 - 11

AbbreviationsHS: Hospital stay, Adm: admission, SOFA: Sequential organ failure assessment, SCr: serum creatinine

IRRIV SCORE®

ROC curve for predicting RRT by IRRIV Score

AUC of 0.81.

IRRIV SCORE®

Calculated probability of staying free from RRT with increasing Score points

The red line marks 3.5 in score points.

IRRIV SCORE®

Intermittent HD in Critically Ill Patients

Advantages

• Lower workload ?

• Patient free time from ET

Limitations

• Severe clinical intolerance

• Fluid restriction required

• Limited efficiency (DPK)

• Dialysis nurse required

CRRT in Critically Ill Patients

Advantages

• Excellent Clinical Tolerance

• Optimal Fluid Control

• Optimal uremic Control

• Excellent Homeostatic Control

• Continuous Clearance

Limitations

• Long term exposure to EC

• Continuous anticoagulation

• Cost and work load

Therapies are not one against the other

Don’t use old studies to compare new treatment

Whatever treatment is used, use it at its best performance

Be flexible and try to prescribe the right therapy for the right patient

Be ready to cross over from one treatment to another

Make sure you are not underdialyzing the patient

The ideal study will never be done

Modality

Facts1) RRT is a cornerstone for the therapy of of AKI in the ICU

2) Indications have changed over the years (replacement vs support)

3) Mortality has changed over the years and so did the case mix

4) We still have a number of unresolved issues or controversies

a) Timing for therapy start and stop

b) Correct prescription (Dose and Fluid balance)

c) Modality and Schedule

d) Monitoring and delivery

e) Special treatments for special cases ADEQUACY?

ADEQUACYLet’s agree on the meaning of the term

AD AEQUATUM = Equal to ……..

Are we really able to obtain results similar to those achieved by the human kidney?

Are we confusing the term “Adequate” with “minimal or sufficient” ?

I personally would define adequate a treatment when further improvements will not result in further benefit. So far adequacy has been identified by the concept of dose (index, marker molecules).

Dose of Dialysis

Extracorporeal HemodialysisS

u r

v i

v a

l

E.D.T.A Proceedings, E.D.T.A Proceedings, 3,122, 19663,122, 1966

…….……. Dialysis for chronic renal Dialysis for chronic renal failure is no longer experimental. failure is no longer experimental. The results speak for themselves. The results speak for themselves.

Belding H. ScribnerBelding H. Scribner

Alwall – Kolff andScribner et Al, 1966

Dose of Dialysis (Urea)


u r

v i

v a

l

Alwall – Kolff and Scribner et Al, 1966

THE MECHANISTIC ANALYSIS

% F

ailu

re

70

60

50

40

30

20

10

0.4 .5 .6 .7 .8 .91.0 1.1 1.2 1.3 1.4 1.5

Gotch & Sargent

Av 0.57

Av 0.13

Kt/V

Keshaviah

NCDS: Gotch & Sargent 1985



u r

v i

v a

l

Dose vs Outcome Studies

Alwall – Kolff andScribner et Al, 1966


HEMODIALYSIS DOSE and OUTCOMESHEMODIALYSIS DOSE and OUTCOMES

DIALYSIS DOSE (Urea)DIALYSIS DOSE (Urea)

Morbidity and Mortality in ESRD PatientsMorbidity and Mortality in ESRD Patients

Owen et al. 1993: URR and the albumin level predict mortalityOwen et al. 1993: URR and the albumin level predict mortality in HDin HD

Collins et Al. 1994: Urea Index predicts Long Term HD resultsCollins et Al. 1994: Urea Index predicts Long Term HD results

Hakim et Al. 1994: Effects of Dialysis Dose on Morbidity and MHakim et Al. 1994: Effects of Dialysis Dose on Morbidity and Mortality in HDortality in HD

Parker et Al. 1994: Improved survival in Hd with higher treatmeParker et Al. 1994: Improved survival in Hd with higher treatment dosesnt doses



u r

v i

v a

l


Alwall Kolff andScribner et Al, 1966


Hemo Study



u r

v i

v a

l


Alwall Kolff andScribner et Al, 1966


Hemofiltration Trials1982-1990

Dose of Dialysis (urea and flux)


u r

v i

v a

l

Treatment Flux ?Incident Patients?Membrane Flux

Hemo Study

1.241.241.241.24

REFREF REFREF

0.50.5

1.01.0

1.51.5

2.02.0

HighHigh--FluxFlux LowLow--FluxFlux BleachBleach No BleachNo Bleach

†† Adjusted for demographics,Adjusted for demographics, comorbiditiescomorbidities, BMI,, BMI, creatininecreatinine, albumin, unit type, and bleach (left panel) , albumin, unit type, and bleach (left panel) or flux (right panel); patients reusing only por flux (right panel); patients reusing only p--values and 95% confidence intervals by bootstrap methodvalues and 95% confidence intervals by bootstrap method

Adjusted Mortality RiskAdjusted Mortality Risk†† for Synthetic Membranesfor Synthetic Membranes

RR (95% CI)RR (95% CI)

Synthetic MembraneSynthetic Membrane

p=0.04 p=0.04

USRDS 1999 Courtesy of F. Port

MPO StudyVariable HD online HDF p

Time on RRT (years) 4.97+4.94 6.61+5.05 > 0.001

Variable online HDF p

Time on RRT (years) 4.97+4.94 6.61+5.05 > 0.001

VariableVariableVariable HDHD online HDFonline HDFonline HDF ppp

Time on RRT (years)Time on RRT (years)Time on RRT (years) 4.97+4.944.97+4.944.97+4.94 6.61+5.056.61+5.056.61+5.05 > 0.001> 0.001< 0.001

Variable HD on-line HDF

p

Treatment Time (min/s.) 241+20 246+20 < 0.001

Treatment Frequency > 3 s./wk (%)

NS

Mean Blood Flow ( mL/min) 325+47 331+50 NS

Mean Dialysate Flow (mL/min) 506+45 543+99 < 0.001

Equil Kt/V 1.43+0.18 1.48+0.20 < 0.001

High - Flux Polysulfone (%) 97.9 100

Variable HD on-line HDF

p

Treatment Time (min/s.) 241+20 246+20 < 0.001

Treatment Frequency > 3 s./wk (%)

NS

Mean Blood Flow ( mL/min) 325+47 331+50 NS

Mean Dialysate Flow (mL/min) 506+45 543+99 < 0.001

Equil Kt/V 1.43+0.18 1.48+0.20 < 0.001

High -Flux Polysulfone (%) 97.9 100

VariableVariableVariable HDHDHD on-line HDF

on line HDF

onlineHDF ppp

Treatment Time (min/s.)Treatment Time (min/s.)Treatment Time (min/s.) 241+20241 20241 20 246+20246 20246 20 < 0.001< 0.001< 0.001

Treatment Frequency > 3 s./wk (%)Treatment Frequency > 3 s./wk (%)Treatment Frequency > 3 s./wk (%)

NSNSNS

Mean Blood Flow ( mL/min)Mean Blood Flow ( mL/min)Mean Blood Flow ( mL/min) 325+47325+47325+47 331+50331+50331 50 NSNSNS

Mean Dialysate Flow (mL/min)Mean Dialysate Flow (mL/min)Mean Dialysate Flow (mL/min) 506+45506 45506 45 543+99543+99543+99 < 0.001< 0.001< 0.001

Equil Kt/VEquil Kt/VEquil Kt/V 1.43+0.181.43 0.181.43 0.18 1.48+0.201.48 +0.201.48 +0.20 < 0.001< 0.001< 0.001

High -Flux Polysulfone (%)High - Flux Polysulfone (%)High - Flux Polysulfone (%) 97.997.997.9 100100100

+

+

+ +

+

4.7 4.8

High - Flux Polysulfone (%) 97.9 100High - Flux Polysulfone (%)High - Flux Polysulfone (%)Death - Risk Reduction (%) 97.997.9 100100 - 35 %

Dose of Dialysis (Urea and beyond)


u r

v i

v a

l

Treatment Flux Incident Patients

Membrane Flux

Race &Genetics

Body Comp (V)

Gender

Dialysisduration

Diabetes& CVD

Tx Time

Frequency of Tx

Dose of Dialysis (Urea and Beyond)

Sur

viva

l + q

ualit

y of

Life

Correction of Anemia

Extracorporeal Hemodialysis

Dose of Dialysis (urea and flux)

PERITONEAL DIALYSISS

u r

v i

v a

l

ADEMEX Study

CANUSA Study

Breaking Point1.7 ? 2.0?

DIETARY PROTEIN INTAKE VERSUS Kt/VDIETARY PROTEIN INTAKE VERSUS Kt/V

0.0.55 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5

0.20.2

0.40.4

0.60.6

0.80.8

11

1.21.2

1.41.4

Weekly Kt/VWeekly Kt/V

D P

I (

g/K

g/24

h)

D P

I (

g/K

g/24

h)

0.00.00.00.0

CAPDCAPD

HDHD

SERUM ALBUMIN CONCENTRATION VERSUS Kt/VSERUM ALBUMIN CONCENTRATION VERSUS Kt/V

0.40.4 0.80.8 1.21.2 1.61.6 2.02.0 2.42.4 2.82.8

1.01.0

2.02.0

3.03.0

4.04.0

5.05.0

6.06.0

0.00.00.00.0

R=0.987R=0.987

R=0.351R=0.351

Weekly Kt/VWeekly Kt/V

Alb

um

in (

g/L

)A

lbu

min

(g/

L)

1.71.7

1994

Dose of Dialysis (Urea + ?) L/h

AKI and CRRTS

u r

v i

v a

l

0.3 0.6 0.9 1.5 2.5 3.5

Stork M, et Al. The Lancet 1991;337:452-455.

Ronco et Al, The Lancet 356, 1, 26-30, 2000

Stork M, et Al. The Lancet 1991;337:452-455.

10090

80706050

40302010

0Uf = < 7 l/24h Uf = 7.5 l/24h Uf = 15 l/24h

p < 0.05

Sur

viva

l %

100

90

80

70

60

50

40

30

20

10

0Group 1(n=146)( Uf = 20 ml/h/Kg)

Group 2 (n=139)( Uf = 35 ml/h/Kg)

Group 3 (n=140)( Uf = 45 ml/h/Kg)

p < 0.001 p n..s.

p < 0.001



Tolwani et Al, JASN 2008 Palewsky et Al, NEJM 2008

Dose of Dialysis (ml/Kg/hr)

AKI and CRRTS

u r

v i

v a

l

Bellomo et Al, NEJM 2009

Saudan et Al, KI 2006Presence of SepsisEarly Intervention

Honoré et Al. CCM, 2002

10 20 30 40 50 60 70 80

Stork M, et Al. The Lancet 1991;337:452-

455.

Dose of Dialysis (Urea and Beyond)

Renal Replacement Therapy in AKIS

u r

v i

v a

l Dose-Dependent Region

Practice-Dependent RegionBreaking

Point?

QUESTIONS

• Adequacy for what?

• What is the task and target of therapy?

IndicationsRenal Replacement

TherapyRenal Support

Therapy

“Absolute”

Life Threatening conditions

“Relative”

Volume removal in FO patients

Immuno-modulation in sepsis

Nutrition support

Cancer chemotherapy

Attenuate ARDS-induced respiratory acidosis

Volume homeostasis in multi-organ dysfunction/failure

Solute control

Homeostatic control

Acid-base regulation

QUESTIONS



• Is adequacy target the same for different patients?

RRT MORTALITY IN AKI%

Mor

talit

y

100

80

60

40

20

0Kidney K + 1 K + 2 K + 3

Number of failing organs

A PROBLEM OF SEVERITY SCORE

Fluid Balance

Ris

k of

Com

plic

atio

ns

Restrictive Fluid protocols

Dehydration

Liberal Fluid protocols

Overhydration

HypotensionTachycardia

ShockOrgan hypoperfusion

OliguriaRenal Dysfunction

Optimal Status

HypertensionPeripheral Edema

Impaired pulmonary exchanges

Organ CongestionRenal Dysfunction

ProceduresDrugsR R T

Normal Heart

Diseased Heart

Fluid Protocols & Balance

CRRT: Impact on Outcomes

Severity of Disease

Sur

viva

l % High Dose (CRRT)

Low Dose(IHD)

The Cleveland Clinic Observation

100

90

80

70

60

50

40

30

20

10

0

Are patients all equal?

Does it make sense to treat them all with the same drug?

What about dialysis dose?

Dose A Dose B Dose C

Patients with hypercatabolism

Patients with hypercatabolism

Urea Kinetics

QUESTIONS




• Are adequacy targets constant over time?

F O %Azotemia

Admission Admission

Day 1 Day 3 Day 5 Day 7 Day 1 Day 3 Day 5 Day 7

60

50

40

30

20

10

0

120

100

80

60

40

20

0

Metabolism and Volume

0

32

30

28

26

24

22

20

18

Hours of observation

HC

O3

(mE

q/l)

Bicarbonate levels in CVVH and Daily HD

6 12 18 24 30 36 42 48

16

14

D Short HD

CVVH

D Ext.HD

QUESTIONS





• Are prescription and delivery the same thing?

Vicenza Course International Surveys

How do you prescribe therapy?

n. 345

n. 564

1998 2004

13%

17%

57%

13%

Blood flow Kt/V ?I do not know Effluent

CRRT Prescription vs DeliveryVenkataraman et al, J Crit Care, 2002

Prescribed Dose (ml/kg/hr)

Delivered Dose (ml/kg/hr)

Time/Day (hours)

24.56.7

16.65.4 16.13.5

68% of

prescribed dose

67% of total

hours in day

0

10

20

30

40

50

60<

5

5-1

0

10

-15

15

-20

20

-25

25

-30

30

-35

35

-40

40

-45

45

-50

50

-55

55

-60

60

-65

65

-70

70

-75

>=

75

Dose of CRRT (mL/Kg/hr)

Pa

tien

ts (

%)

Delivered dose Prescribed dose

DoReMi Database (N=865)

Median prescribed = 34 mL/kg/hMedian delivered = 27 mL/kg/h

Ronco et al, 2009

Dose of CRRT (mL/kg/h)

Pa

tient

s (%

)

51

Delivered dose of CRRT

CVVHD CVVHDF CVVH

ml/

kg/h

25

40

32

Adjusted for 24 hrs

QUESTIONS






• Are adequacy targets similar for different modalities

Treatments for extracorporeal volume removal

Technique Frequency

• Ultrafiltration• Hemofiltration• Hemodialiysis• Hemodiafiltration

• Isolated• Intermittent• Daily• Continuous

120

100

80

60

40

20

0

BU

N (

mg

/dl)

Hours of treatment0 6 12 18 24 30 36 42 48 54

D short HD

CVVH

D Ext. HD

Pl. Na+

140

140

Uf

2 L

10 L

Na+ Rem

280

1400

Repl.

0

8 L

R Na+

- - -

130

Fluid Bal.

- 2 Kg

- 2 Kg

Na+ Bal.

- 280 mmol

- 360 mmol

Continuous Hemofiltration allows for correction of sodium and water disorders by dissociating water and sodium removal

Composition of fluid removed

0

Hours of observation

6 12 18 24 30 36 42 48

+20

+100

-10

-20

-30

11010090807060

Mean

5040

Art. Press.(mmHg)

Blood VolumeVariation

(%)

SCUFUf = 3050 ml

UF

Uf = 3030 ml

Hemodynamic response

UF beginning UF end

Re l a t i ve

Changes

Blood Volume

Blood Pressure

a

a1

Uf / Refilling rate related hypotension

Overall ECFV related hypotension

Sequential BNP +BIVA measurements

CRRT-Associated Mortality in Major RCTs

Clinical Trial Comparison APACHE II Endpoint Mortality

Ronco et al (2000) CRRT Dose 22 15-day2 59%3

Mehta et al (2001) IHD vs CRRT 25.5 Hospital 66%

Augustine et al (2004) IHD vs CRRT - Hospital 68%

Saudan et al (2006) CRRT Dose 25 90-day 66%3

Vinsonneau et al (2006) IHD vs CRRT 25 60-day 68%

Lins et al (2008) IHD vs CRRT 27 Hospital 58%

Tolwani et al (2008) CRRT Dose 26 Hospital 60%3

ATN Trial (2008) Dialysis Dose 26.3 60-day 52.5%4

RENAL Trial (2009) CRRT Dose ~261 90-day 45%

1: APACHE III score 102-103 2: After CRRT cessation3: Mortality in low-dose group 4: Overall (CRRT + IHD) mortality

Comparison of RENAL with ATN

Variable RENAL VA/NIH

Mortality day 90 44.7%

Mortality day 60 52.5%

RRT days (at 28 days) 7.4 13.1

Hospital LOS (days) 25.2 48

Dialysis dependence @day 28 13.3% 45.2%

Dialysis dependence @day 60 24.6%

Dialysis dependence @day 90 5.6%

0

.2

.4

.6

.8

1

0 20 40 60 80 100

IRRT

CRRT

days

Recovery from dialysis dependenceR

ecov

ery

from

dia

lysi

s de

pend

ence

Hypotension: IRRT: 24.0% CRRT: 11.1%

Ucino et Al Int. J Artif Organs 2007

RRT dependent on day 90

RENAL Ghent FINNAKI ATN0%

10%

20%

30%

5.6%

10.4%11.5%

24.6%

QUESTIONS






• Are adequacy targets similar for different modalities

• Should I consider miltiple parameters to define adequacy?

Timing and Schedule of Tx

Restoration of Homeostasis

Urea-based Dosing

Control of inflammation

Organ Substitution/Support

Volume Control

Membrane Sieving

Adequacy of Extracorporeal Support

Acid-Base Balance

Spectrum of Solute MV

Limitation of Oxidant stress

Kt/V or ml/h/Kg

Middle Molecules

Cardiovascular

P & Ca

Nutrition

Severity scores

Homeostasis

Coagulation

Contr. of sepsis

Fluid balance

0

0.5

1

Multidimensional View of Adequacy

Kt/V or ml/h/Kg

Middle Molecules

Cardiovascular

P & Ca

Nutrition

Severity scores

Homeostasis

Coagulation

Contr. of sepsis

Fluid balance

0

0.5

1

Adequacy: Recipe not Index

SPECIAL FIBERS AND FILTERS HAVE BEEN DESIGNED FOR SPECIAL CONDITIONS AND PATIENTS

Minifilters

Ronco C, Brendolan A, Bragantini L, Chiaramonte S, Feriani M, Frigiola A, Menicanti L, La Greca G: Treatment of acute renal failure in newborns by Continuous Arterio-Venous Hemofiltration.

Kidney International, 1984

Apache SOFA

M O S T Score

%

Mor

talit

y

100

80

60

40

20

0

RRT1 2 3 4 5

RRTSCUF

RRTSCUFECLS

RRTSCUFECLSLiverS

RRTSCUFECLSLiverS

HVHF-CPFA

Kidney K + 1 K + 2 K + 3 K + 3 + Sepsis

Special treatments for special cases

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