1. Holistic Approach to Treatment Adequacy in AKI
Claudio Ronco, MD Department of Nephrology, St. Bortolo Hospital, International Renal Research Institute Vicenza - Italy

2. AKI: historical notices
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.

3. 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%.

6. Courtesy of Coll. Dr: Paul Teschan

7. AKI: historical notices
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.

9. AKI: Changing Pattern Mortality 54 % Mortality 53 %
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.
Vicenza Database 1974 – Total number of incident cases = 48
Vicenza Database 1995 – Total number of incident cases = 525
Mortality 54 %
Mortality 53 %

10. Facts RRT is a cornerstone for the therapy of of AKI in the ICU
Indications have changed over the years (replacement vs support)
Mortality has changed over the years and so did the case mix
We still have a number of unresolved issues or controversies
Timing for therapy start and stop
Correct prescription (Dose and Fluid balance)
Modality and Schedule
Monitoring and delivery
Special treatments for special cases

11. We need additional clinical studies!
About timing
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 initiation
We need additional clinical studies! 11

12. RCT: RR 0.64 (95% CI, 0.40-1.05) Cohort: RR 0.72 (95% CI, 0.64-0.82)
Division of Nephrology, Hospital das Clinicas, University of São Paulo, São Paulo, Brazil.
Mortality.
Seabra et al AJKD 2008 12

13. Electronic Sniffers and RIFLE Alert
Confirm
You reached RIFLE class “RISK”
Baseline Creatinine = 0.9
Actual creatinine = 1.55 x Baseline

14. IRRIV SCORE® IRRIV Score 0.61 1 0.57 2 0.60 0.73 0.52 1.5 0.63 0.47
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
Urinary output * Lowest on first day of ICU
<= 40 ml/h
SOFA Renal * On first day of ICU
>= 2
0.73
Invasive Mechanical Ventilation On first day of ICU
No MV
0.52
1.5
Change of SCr. during ICU stay (mg/dl) * (HS-Adm)
>= mg/dl
0.63
Fluid Accumulation * 
>= 10 %
0.47
IRRIV Score
To predict RRT and define late Initiation
>= 3.5 pt.
including one renal dysfunction markers (*)
0.81
Total:
Abbreviations
HS: Hospital stay, Adm: admission, SOFA: Sequential organ failure assessment, SCr: serum creatinine

15. ROC curve for predicting RRT by IRRIV Score
AUC of 0.81.

16. The red line marks 3.5 in score points.
Calculated probability of staying free from RRT with increasing Score points
IRRIV SCORE®
The red line marks 3.5 in score points.

17. 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

18. 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

19. Modality 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

20. Facts
RRT is a cornerstone for the therapy of of AKI in the ICU
Indications have changed over the years (replacement vs support)
Mortality has changed over the years and so did the case mix
We still have a number of unresolved issues or controversies
Timing for therapy start and stop
Correct prescription (Dose and Fluid balance)
Modality and Schedule
Monitoring and delivery
Special treatments for special cases
ADEQUACY?

22. AD AEQUATUM = Equal to ……..
ADEQUACY
Let’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).

23. Extracorporeal Hemodialysis
S u r v i v a l
Alwall – Kolff and
Scribner et Al, 1966
Dose of Dialysis

24. Extracorporeal Hemodialysis
THE MECHANISTIC ANALYSIS
% Failure 70 60 50 40 30 20 10 .4 .5 .6 .7 .8 .9
1.0
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
S u r v i v a l
Alwall – Kolff and
Scribner et Al, 1966
Dose of Dialysis (Urea)

25. Extracorporeal Hemodialysis
Dose vs Outcome Studies
S u r v i v a l
NCDS: Gotch & Sargent 1985
Alwall – Kolff and
Scribner et Al, 1966
Dose of Dialysis (Urea)

26. Extracorporeal Hemodialysis
Hemo Study
S u r v i v a l
Dose vs Outcome Studies
NCDS: Gotch & Sargent 1985
Alwall Kolff and
Scribner et Al, 1966
Dose of Dialysis (Urea)

27. Extracorporeal Hemodialysis
Hemofiltration Trials
S u r v i v a l
Dose vs Outcome Studies
NCDS: Gotch & Sargent 1985
Alwall Kolff and
Scribner et Al, 1966
Dose of Dialysis (Urea)

28. Extracorporeal Hemodialysis
Variable HD
online HDF p
Time on RRT (years)
4.97 +
4.94
6.61
5.05
> 0.001
< 0.001 on -
line
HDF
Treatment Time (min/s.)
241 20
246
Treatment Frequency > 3 s./wk
(%) NS
Mean Blood Flow ( mL
/min)
325 47
331 50
Mean
Dialysate
Flow (
506 45
543 99
Equil Kt/V
1.43
0.18
1.48
0.20
High
Flux
Polysulfone
97.9
100
online
4.7
4.8
Death
Risk
Reduction
- 35 %
MPO Study
Treatment Flux ?
Incident Patients?
Membrane Flux
Hemo Study
S u r v i v a l
Dose of Dialysis (urea and flux)

29. Extracorporeal Hemodialysis
Membrane Flux
Dialysis
duration
Treatment Flux
Incident Patients
Body
Comp (V)
Tx Time
Race &
Genetics
Gender
Diabetes
& CVD
Frequency
of Tx
S u r v i v a l
Dose of Dialysis (Urea and beyond)

30. Extracorporeal Hemodialysis
Correction of Anemia
Survival + quality of Life
Dose of Dialysis (Urea and Beyond)

31. Dose of Dialysis (urea and flux)
PERITONEAL DIALYSIS
Breaking Point
1.7 ? 2.0?
1994
ADEMEX Study
S u r v i v a l
CANUSA Study
Dose of Dialysis (urea and flux)

32. AKI and CRRT
Ronco et Al, The Lancet 356, 1, 26-30, 2000
Stork M, et Al. The Lancet 1991;337:
100 90 80 70 60 50 40 30 20 10 Uf
= < 7 l/24h
= 7.5 l/24h
= 15 l/24h
p < 0.05
Survival %
100 90 80 70 60 50 40 30 20 10
Group 1(n=146) ( Uf
= 20 ml/h/Kg)
Group 2 (n=139)
= 35 ml/h/Kg)
Group 3 (n=140)
= 45 ml/h/Kg)
p < 0.001
p n..s.
Ronco et Al, The Lancet 356, 1, 26-30, 2000
S u r v i v a l
Stork M, et Al. The Lancet 1991;337:
Dose of Dialysis (Urea + ?) L/h

33. AKI and CRRT S u r v i v a l Dose of Dialysis (ml/Kg/hr)
Presence of Sepsis
Early Intervention
Honoré et Al. CCM, 2002
Saudan et Al, KI 2006
Ronco et Al, The Lancet 356, 1, 26-30, 2000
Bellomo et Al, NEJM 2009
S u r v i v a l
Tolwani et Al, JASN Palewsky et Al, NEJM 2008
Stork M, et Al. The Lancet 1991;337: 10 20 30 40 50 60 70 80
Dose of Dialysis (ml/Kg/hr)

34. Dose-Dependent Region
Renal Replacement Therapy in AKI
Breaking Point?
Practice-Dependent Region
Dose-Dependent Region
S u r v i v a l
Dose of Dialysis (Urea and Beyond)

36. QUESTIONS
Adequacy for what?
What is the task and target of therapy?

37. Renal Replacement Therapy
Indications
Renal Replacement Therapy
Renal 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

38. QUESTIONS Adequacy for what? What is the task and target of therapy?
Is adequacy target the same for different patients?

39. RRT MORTALITY IN AKI % Mortality Number of failing organs
A PROBLEM OF SEVERITY SCORE
100 80 60 40 20
% Mortality
Kidney
K + 1
K + 2
K + 3
Number of failing organs

40. Fluid Protocols & Balance
Restrictive Fluid protocols
Liberal Fluid protocols
Diseased Heart
Procedures
Drugs
R R T
Normal Heart
Risk of Complications
Hypotension
Tachycardia
Shock
Organ hypoperfusion
Oliguria
Renal Dysfunction
Hypertension
Peripheral Edema
Impaired pulmonary
exchanges
Organ Congestion
Renal Dysfunction
Optimal Status
Dehydration
Fluid Balance
Overhydration

41. CRRT: Impact on Outcomes
The Cleveland Clinic Observation
100 90 80
High Dose (CRRT) 70 60
Survival % 50
Low Dose
(IHD) 40 30 20 10
Severity of Disease

42. Does it make sense to treat them all with the same drug?
Are patients all equal?
Does it make sense to treat them all with the same drug?
What about dialysis dose?

43. Patients with hypercatabolism Patients with hypercatabolism
Urea Kinetics
Dose A
Dose B
Dose C

44. 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?

45. Metabolism and Volume Azotemia F O % 120 100 80 60 40 20 60 50 40 3060 50 40 30 20 10
Day Day Day Day 7
Day Day Day Day 7
Admission
Admission

46. Bicarbonate levels in CVVH and Daily HD32 30
D Short HD 28
D Ext.HD 26
HCO3 (mEq/l) 24
CVVH 22 20 18 16 14 6 12 18 24 30 36 42 48
Hours of observation

47. 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?

48. Vicenza Course International Surveys How do you prescribe therapy?
1998
2004
n. 345
n. 564

49. CRRT Prescription vs Delivery Venkataraman et al, J Crit Care, 2002
24.56.7
16.65.4
16.13.5
68%
of prescribed dose
67%
of total hours in day

50. DoReMi Database (N=865) Patients (%) Dose of CRRT (mL/kg/h)
Ronco et al, 2009
Median delivered = 27 mL/kg/h
Median prescribed = 34 mL/kg/h
Patients (%)
Dose of CRRT (mL/kg/h)

51. Delivered dose of CRRT ml/kg/h Adjusted for 24 hrs CVVHD CVVHDF CVVH40 32 25
Adjusted
for 24 hrs
CVVHD CVVHDF CVVH 51

52. 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

53. Treatments for extracorporeal volume removal
Technique
Frequency
Ultrafiltration
Hemofiltration
Hemodialiysis
Hemodiafiltration
Isolated
Intermittent
Daily
Continuous

54. D short HD CVVH D Ext. HD BUN (mg/dl) Hours of treatment 120 100 80 6040
D Ext. HD 20 6 12 18 24 30 36 42 48 54
Hours of treatment

55. Composition of fluid removed
Continuous Hemofiltration allows for correction of sodium and water disorders by dissociating water and sodium removal
Pl. Na+
140 Uf
2 L
10 L
Na+ Rem
280
1400
Repl.
8 L
R Na+
- - -
130
Fluid Bal.
- 2 Kg
Na+ Bal.
- 280 mmol
- 360 mmol

56. Hemodynamic response Blood Volume Variation (%) Mean Art. Press.
Hours of observation 6 12 18 24 30 36 42 48
+20
+10
-10
-20
-30
110
100 90 80 70 60
Mean 50 40
Art. Press.
(mmHg)
Blood Volume
Variation
(%)
SCUF
Uf = 3050 ml UF
Uf = 3030 ml

57. Sequential BNP +BIVA measurements
Uf / Refilling rate
related hypotension
Overall ECFV
related hypotension
Re l a t i ve
Changes
Blood Pressure
Blood Volume a a1
Sequential BNP +BIVA measurements
UF beginning
UF end

58. CRRT-Associated Mortality in Major RCTs
Clinical Trial Comparison APACHE II Endpoint Mortality Ronco et al (2000) CRRT Dose day %3
Mehta et al (2001) IHD vs CRRT Hospital %
Augustine et al (2004) IHD vs CRRT Hospital %
Saudan et al (2006) CRRT Dose day %3
Vinsonneau et al (2006) IHD vs CRRT day %
Lins et al (2008) IHD vs CRRT Hospital %
Tolwani et al (2008) CRRT Dose Hospital %3
ATN Trial (2008) Dialysis Dose day %4
RENAL Trial (2009) CRRT Dose ~ day %
1: APACHE III score : After CRRT cessation
3: Mortality in low-dose group : Overall (CRRT + IHD) mortality

59. 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 28
13.3%
45.2%
Dialysis 60
24.6%
Dialysis 90
5.6% 59

60. Recovery from dialysis dependence1
CRRT
Recovery from dialysis dependence .8 .6
IRRT .4
Hypotension: IRRT: %
CRRT: 11.1% .2 20 40 60 80
100
days
Ucino et Al Int. J Artif Organs 2007

61. RRT dependent on day 90

62. 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?

63. Organ Substitution/Support Limitation of Oxidant stress
Adequacy of Extracorporeal Support
Urea-based Dosing
Membrane Sieving
Control of inflammation
Timing and Schedule of Tx
Organ Substitution/Support
Spectrum of Solute MV
Restoration of Homeostasis
Volume Control
Limitation of Oxidant stress
Acid-Base Balance 63

64. Multidimensional View of Adequacy

65. Multidimensional View of Adequacy

66. Multidimensional View of Adequacy

67. Multidimensional View of Adequacy

68. Adequacy: Recipe not Index

69. 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

71. Special treatments for special cases
Apache SOFA 1 2 3 4 5
M O S T Score
RRT
RRT
SCUF
RRT
SCUF
ECLS
RRT
SCUF
ECLS
LiverS
RRT
SCUF
ECLS
LiverS
HVHF-CPFA
100 80 60 40 20 $
% Mortality
Kidney
K + 1
K + 2
K + 3
K Sepsis

72. Look on You tube