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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%.
AKI: historical notices
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.
AKI: historical notices
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)
Extracorporeal HemodialysisS
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
Dose of Dialysis (Urea)
Extracorporeal HemodialysisS
u r
v i
v a
l
Dose vs Outcome Studies
Alwall – Kolff andScribner et Al, 1966
NCDS: Gotch & Sargent 1985
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
Dose of Dialysis (Urea)
Extracorporeal HemodialysisS
u r
v i
v a
l
Dose vs Outcome Studies
Alwall Kolff andScribner et Al, 1966
NCDS: Gotch & Sargent 1985
Hemo Study
Dose of Dialysis (Urea)
Extracorporeal HemodialysisS
u r
v i
v a
l
Dose vs Outcome Studies
Alwall Kolff andScribner et Al, 1966
NCDS: Gotch & Sargent 1985
Hemofiltration Trials1982-1990
Dose of Dialysis (urea and flux)
Extracorporeal HemodialysisS
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)
Extracorporeal HemodialysisS
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
Ronco et Al, The Lancet 356, 1, 26-30, 2000
Ronco et Al, The Lancet 356, 1, 26-30, 2000
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
• Adequacy for what?
• What is the task and target of therapy?
• 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
• Adequacy for what?
• What is the task and target of therapy?
• Is adequacy target the same for different patients?
• 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
• Adequacy for what?
• What is the task and target of therapy?
• Is adequacy target the same for different patients?
• Are adequacy targets constant over time?
• 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
• Adequacy for what?
• What is the task and target of therapy?
• Is adequacy target the same for different patients?
• Are adequacy targets constant over time?
• Are prescription and delivery the same thing?
• 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
• Adequacy for what?
• What is the task and target of therapy?
• Is adequacy target the same for different patients?
• Are adequacy targets constant over time?
• Are prescription and delivery the same thing?
• 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
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
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
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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