Il futuro della terapia emodialitica:tra innovazione e disponibilità di risorse

1. Il futuro della terapia emodialitica:tra innovazione e
disponibilità di risorse
Antonio Santoro
U.O. di Nefrologia, Dialisi ed Ipertensione
Azienda Ospedaliero-Universitaria di Bologna
Policlinico S.Orsola-Malpighi
- Bologna -

2. L’idea che si fa strada è che ormai
la battaglia per ottenere una nuova
assicurazione sanitaria pubblica
sia definitivamente perduta. Lo
ammette con rassegnazione i
principali sostenitori di questa
opzione.
Sanità, a rischio la riforma Obama
Repubblica — 17 agosto 2009 pagina 14 sezione:
POLITICA ESTERA

3. INVESTING IN DIALYSIS TECHNOLOGY?
•Limited resources
•Rigidity of the accounting system
•Excessive expense for the hospital treatment to the
detriment of territorial/home care
•Cost of technology
•Training of personnel
•Ageing population (both incident and
prevalent)
•High comorbidity / mortality
•Disappointing results of some
clinical trials
ALL RUNS AGAINST

4. •
1940 1960 today
THE UNDENIABLE TECHNOLOGICAL PROGRESS IN DIALYSIS

5. 325
275
225
175
HemodialysisHemodialysis PeritonealPeritoneal dialysisdialysis
400
300
200
100
0
80 84 88 92 96 00
80 84 88 92 96 00
MORTALITY RATES IN INCIDENT ESRD PATIENTS: 1980-2000
Deathsper1,000ptyearsatrisk
Deathsper1,000ptyearsatrisk
1st year 2nd year 4th year3rd year 5th year
United States Renal Data System
THE UNDENIABLE CLINICAL PROGRESS IN DIALYSIS

6. ANNUAL MORTALITY BY CONTINENT
6.6
15.6
21.7
0
10
20
30
40
Japan Europe USA
Goodkin DA et al, J Am Soc Nephrol. 2003; 14: 3270-3277
Annual crude mortality, %

7. Main comorbidities in ESRD (worldwide)
0 20 40 60 80 100
Hypertension
Diabetes
Age 60+
Cardiomiopathy
ESA resistance
Electrolytes
disorders
Overweight
Cachexia
Percentage of patients affected by
Min
Max

8. COMORBID CONDITIONS AT BASELINE
29.4
19.2
49.8
25
6.1
45.8
36.5
23.9
36.3
55.2
28.1
34.4
72.7
55.9
83.2
13.7
12.5
18.4
22.5
11.5
26.1
20.1
25.6
45.7
0 20 40 60 80 100
Europe
Japan
US
Diabetes
Perip vasc dis
Cereb vasc dis
Hypertension
Left Vent Hypert
Other card dis
Congestive heart fail
Coronary art dis
Percent of patients, %
Rayner HC et al, Nephrol Dial Transplant 2004; 19: 108-120

9. WHAT ELSE BEYOND THE PATIENT?

10. ANNUAL MORTALITY BY CONTINENT
6.6
15.6
21.7
0
10
20
30
40
Japan Europe USA
Goodkin DA et al, J Am Soc Nephrol. 2003; 14: 3270-3277
Annual crude mortality, %
Conventional
treatements
Shorter treatment times
HDF 0.1%
Reuse
……
Longer treatment times
HDF 4.7 – 17.1%
(DOPPS 3)

11. Hypertension
Hypotension
Vascular access
failure
(Probability of vascular access
failure within one year)
Amyloidosis
(C-reactive P ≥ 10 mg/dL)
Micro.macro
inflammation
Hospitalization
(Rate per patient-year)
•Mittal SK, Clin Nephrol,1999, 51 (2), 77-82
•Chazot C et al, ND &T, 1995, 10, 831-837
•Reyner HC et al, Kidney Int, 2003, 63 , 323–330
•Stenvinkel P, Kidney Int., Vol. 62 (2002), 1791–1798
•Rayner HC et al, ND & T (2004) 19: 108–120.
•O’Brien T, AJKD, 2008, 51 (1), S1, S137-154
•De Santo G et al, AJKD, 2001, 38 (4) S1, S38-S46.
•Agarwal et al, AJKD, 2008, 51, (2), 242-254
•Lehnert H et al, ND& T, 1996, 11, 2004-2007
1.1
HD-related complications in Conventional HD

12. DIALYSIS INNOVATIONS
1990-2010
New membranes
Nanotechnology:
membrane pore size,
fiber diameter,
surface treatment
Monitoring/controlling systems
blood volume, blood temp,
electrolytes, efficiency…
Variable schedules
short daily,
nocturnal, more
than 3…
Water / Dialysate
on-line preparation
microbiol quality
Different modalities
HDF/HF/AFB/PHF/HFR

13. Incremental cost and incremental life expectancy
relative to current practice under baseline
assumptions.
Lee CP. et al. JASN 2008;19:1972
Incremental Life Expentancy (months)
Incrementallifetimecost($)

14. INVESTING IN DIALYSIS?
•Limited resources
•Rigidity of the accounting system
•Excessive expense for the hospital treatment to the
detriment of territorial/home care
•Cost of technology
•Training of personnel
•Ageing population (both incident and
prevalent)
•High comorbidity / mortality
•Disappointing results of some
clinical trials
WHY?WHY?
FOR WHOM?FOR WHOM?
ON WHAT?ON WHAT?

15. WHY SHOULD WE INVEST IN DIALYSIS?
Optimize the correction of the
uremic status and preventing
complications
Continuous growth of the
prevalent population
Reduce the
unphysiology of
dialysis
Improve the quality of life
0
10
20
30
40
50
60
0-2 3-4 5-6 7-8 9-10
Mental health composite Physical health composite
Number of moderate or severe ESAS symptoms
HRQLcompositescore
Inadequate number of transplants /
long waiting time
0
1000
2000
3000
4000
5000
6000
7000
8000
2003 2004 2005
kidney
liver heart
Mean time on waiting list: 3.1 yrs
Death rate on waiting list 1.29%
(Centro Nazionale Trapianti,2006)
IMPROVE SURVIVALIMPROVE SURVIVAL
INVESTING IN DIALYSIS

16. DIALYSIS INNOVATIONS
1990-2010
New membranes
Nanotechnology
membrane pore size,
fiber diameter,
surface treatment
Monitoring/controlling systems
Blood Volume, Blood Temp,
Electrolytes, Efficiency…
Variable schedules
short daily,
nocturnal, more
than 3…
Water / Dialysate
on-line preparation
microbiol quality
Different modalities
HDF/HF/AFB/PHF/HFR
1
2
3

17. DIALYSIS INNOVATIONS
1990-2010
New membranes
Nanotechnology
membrane pore size,
fiber diameter,
surface treatment
Monitoring/controlling systems
Blood Volume, Blood Temp,
Electrolytes, Efficiency…
Variable schedules
short daily,
nocturnal, more
than 3…
Water / Dialysate
on-line preparation
microbiol quality
Different modalities
HDF/HF/AFB/PHF/HFR
1
2
3
WITH WHAT
EVIDENCE TO
SHOW IT IS
WORTHWHILE?

18. NANOCONTROLLED SPINNING TECHNOLOGY:
The coming revolution in molecular manifacturing

19. PROTEIN-LEAKING MEMBRANESc
• To remove hemopoiesis inhibitors
• To remove inflammation mediators
• To remove free light chains
• To reduce “uremic toxicity”

20. Middle molecules & Albumin-bound high MW toxins
b2 microglobulin
adrenomedullin
angiogenin
atrial natriuretic peptide
b endorphin
cholecystokinin
Clara cell protein
complement factor D
cystatin
delta sleep inducing peptide
endothelin
Angiogenin
hyaluronic acid
interleukin 1b
interleukin 6
k-Ig light chain
g-Ig light chain
leptin
methionine enkephalin
neuropeptide
parathyroid hormone
retinol binding protein
tumor necrosis factor
Furancarboxilic acids
(CMPF)
Indoxil-sulfate
Advanced glycation end-
products (AGE)
Advanced oxidation protein
products (AOPP)
Protein poliaminated
polimers (PPP)
AGE-induced peptide-
protein cross-linking
(protein carbonyls)
Leptin
(MW 16 Kd)
MIA SYNDROME

21. Eknoyan et al NEJM, 2002
Low flux membrane
versus
High flux membrane
High Dose: eKt/V 1.45
versus
Standard Dose: eKt/V 1.05
EFFECTS OF DIALYSIS DOSE AND MEMBRANES ON
SURVIVAL IN RDT: THE HEMO STUDY

22. Beneficial but delayed effects of membrane
permeability on mortality
Cheung AK et al, J Am Soc Nephrol, 2003; 14: 3251-3263
HEMO Study
1
0,92
1,05
0,68
0,60
0,70
0,80
0,90
1,00
1,10
1,20
Reference All <3.7yrs >3.7yrs
0.560.23 0.001p
-37%

23. HF synthetic
n = 241
LF synthetic
n = 247
LF semisynthetic
n = 119
LF cellulosic
n = 41
Beneficial effects of High Flux membranes on
survival of HD patients
Krane V et al, Am J Kidney Dis 2007; 49, 267-275
4D
All-cause mortality

24. Kaplan-Meier survival curves for the population of patients with
serum albumin <4 g/dl (Log-rank test P= 0.032)
Locatelli F. et al. J Am Soc Nephrol 20: 645–654, 2009
Patients with serum albumin < 4 g/dl (P=0.032)
High flux membrane
Low flux membrane
0 12 24 36 48 60 72 84
Months
Survivalprobabilityofpatients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
MPO study

25. Copyright restrictions may apply. Okuno, S. et al. 2009
BETA-2-MICROGLOBULIN AND SURVIVAL
All-cause mortality (Kaplan-Mejer) of 490 HD patients, classified
according to lower (<32.2 mg/L, n = 245) and higher (>=32.2 mg/L,
n = 245) beta2-M concentrations

26. 35% reduction of mortality in High
efficiency HDF treated patients
1 1,03
0,93
0,65
0,0
0,2
0,4
0,6
0,8
1,0
1,2
Low Flux HD High Flux HD Low Efficiency
HDF
High Efficiency
HDF
p = 0.68
p =
0.83Ref p = 0.01
Canaud B et al, Kidney Int 2006; 69: 2087-2093
-35%

27. Mortality (all-causes) is reduced in HDF treated
patients
BHD
HDF bags
HDF on-
line
RISCAVID Panichi V et al, Nephrol Dial Transplant. 2008

28. -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10
Difference (%)
P<0.001
P<0.05
P=n.s.
P<0.0001
P=0.019
P=0.04
P=n.s.
(Pozzoni P et al, Hemodial Int, 2006)
Hornberger et al, 1992
Port et al, 2001
Leypoldt et al, 1999
Koda et al, 1997
Locatelli et al, 1999
Eknoyan et al, 2002
Woods et al, 2000
(OR)
(OR)
(OR)
(OR)
(OR)
(OP)
(RCT)
OR observational retrospective
RCT randomized clinical trial
OP observational prospective
Relevance of convective treatments in reducing
mortality risk

29. Selection of studies evaluating the effect of HDF on
cardiovascular instability
HDF: versus HD; no
difference
8-12 L postdilution380 (50 HDF)RandomizedLocatelli 1996
HDF: less hypotensive
episodes
18-22.5 L, method
NA
76Cross-overSchiffl 2007
HDF: less hypotensive
episodes
12 L postdilution11Cross-overDonauer 2003
HDF: versus lfHD; no
difference
60 L mid-dilution44RandomizedWizemann 2000
HDF: less hypotensive
episodes
15.8 L postdilution6Cross-overMovilli 1996
HDF: improved
cardiovascular
stability
18-20 L, method NA8Cross-overMion 1992
OutcomeHDF: Target
convection volume
per session and
method
Number of
patients
DesignReference

30. DIALYSIS HYPOTENSION (FREQUENT OR
OCCASIONAL) AND SURVIVAL
Tiesler et al , ND&T, 2003, 18, 2601-05

31. 0
5
10
15
20
25
Baseline 4M 8M 12M 16M 20M 24M 28M 32M 36M
Dialysishypotensionfrequency(%sessions)
Time (months)
Frequency of dialysis hypotension during the
trial in patients completing the study period
Santoro A. et al. Am J Kidney Dis 2008;52:507-518
HD HF

32. P=0.05
Cumulativesurvival,%
Time (months)
Hemodialysis
Hemofiltration
Survival curves corrected by age of the patients
participating in the trial (Intention-to-treat analysis)
Santoro A. et al. Am J Kidney Dis 2008;52:507-518
Β2-microglobulin
HD: 36.9 mg/dl
HF:23.9 mg/dl
KT/V
HD: 1.42
HF: 1.07

33. SENSORS IN DIALYSIS
Blood volume
monitoring
Blood
temperature
monitoring
Artificial
intelligence
Patient
Dialysis
machine
BIOFEEDBACK
CONTROL
SYSTEMS

34. Blood Pressure/Volume Domain Map during HD and UFBlood Pressure/Volume Domain Map during HD and UF
Dialysis StartDialysis Start Dialysis EndDialysis End
ECFVECFV
RR
ee
ll
aa
tt
ii
vv
ee
CC
hh
aa
nn
gg
ee
ss
SBIASBIA
UFRUFR
TBIATBIA
BVBV
BPBP
HRHR

35. Controller Dialyzer Patient
Blood Volume
Monitor
BV error
Measured BV
+
-
Desired BV
UF set
DC set
UF
DC
BV
Blood Volume Regulation During Hemodialysis,
A. Santoro et al, Am J Kidney Dis, 1998, 32, 5:
738-748
AUTOMATIC BLOOD VOLUME REGULATION

36. 0
20
40
60
80
0 20 40 60 80
Santoro A. et al, Blood volume controlled hemodialysis in hypotension-prone patients:
A randomized, multicenter controlled trial, Kidney Int. 2002, 62, 1034-1045
0
2
4
6
8
10
12
AverageN°.of
collapses
< 5 5 ÷ 8 > 8
Patient ClassStandard HD
Automatic HD
Individual frequency of
hypotension in ACHD
Individualfrequencyof
hypotensioninCHD
DIALYSIS-RELATED SYMPTOMATIC HYPOTENSION

37. 0,0 0,5 1,0 1,5 2,0
Odds ratio with 95% CI
Pooled results on Blood Volume Tracking
1998Santoro
2003
2002
2002
2005
2002
2001
2000
Pooled Odd Ratio
(Peto-Yusuf method *)
N=118 pts
Cagnoli
Deziel
Kooman
Franssen
Santoro
Basile
Ronco
Favour BVT Favour std HD
p<0.001 *
p<0.001
p<0.0001
p=0.004
p<0.05
p<0.001
p<0.01
P<0.01
p<0.01
Santoro A. Biofeedback in dialysis. Blood Purification 2006

38. INTRADIALYTIC BODY TEMPERATURE CONTROL
0
2
4
6
8
10
12
14
Treatment A Treatment B
No.oftreatmentswith
hypotension
Maggiore Q. Pizarelli F.Santoro A.et al. AJKD,2002
0.0 0.5 1.0 1.5 2.0
35
36
37
38
T [°C]
t[h]
Tven
Tbody
-100
0
0.0 0.5 1.0 1.5 2.0
t[h]
E[kJ]
Temperature control
treatment (B treatment)
Energy control,
4 weeks
Temperature control,
4 weeks

39. Selby NM. A systematic review of the clinical effects of reducing dialysate fluid temperature.
NDT 2006;21:1883-1898
Pooled results for intradialytic hypotension
prevention with cool temperature

40. Morbidity
Mortality
EPO
resistance
Vaascular
accessfailure
Vascular
calcification
Hypercataboli
sm
T3
T3
T2
T1
LVH
Hypertension
Arrhythmias
Hypotension
T
Clinical “segments”

41. INVESTING IN DIALYSIS?
•Limited resources
•Rigidity of the accounting system
•Excessive expense for the hospital treatment to the
detriment of territorial/home care
•Cost of technology
•Training of personnel
•Ageing population (both incident and
prevalent)
•High comorbidity / mortality
•Disappointing results of some
clinical trials
PERCHE’?PERCHE’?
FOR WHOM?FOR WHOM?
ON WHAT?ON WHAT?

42. Correct identification of the
target patient:
Everyone?
If not everyone, then who?
Congruous distribution of
the resources:
Research/application priority
HOW SHOULD THE PROBLEM BE DEALT WITH?
Who for?
For the young person, for the
patient awaiting transplant, for the
person with cardiovascular disease,
for the elderly.

43. Researchers
Companies
Hospitals
Universities
LINES OF TECHNOLOGICAL
DEVELOPMENT
COMPANIES
MIXED GROUPS HAVING AN INTERNATIONAL
SCIENTIFIC-TECHNOLOGICAL
ORIENTATION

44. Correct identification of the
target patient:
Everyone?
If not everyone, then who?
Congruous distribution of
the resources:
Research priorities
Performance suitability:
What for whom?
Monitoring of effectiveness:
Results?
HOW SHOULD THE PROBLEM BE DEALT WITH?
PHYSICIANS

45. Evoluzione e necessità di un saltoEvoluzione e necessità di un salto
quanticoquantico
Miniaturizzazione,Miniaturizzazione, NanotecnologieNanotecnologie e Microfluidicae Microfluidica
Miniaturizzazione
significa
trasportabilità,
indossabilità
e forse
impiantabilità i.e.
mobilità
Le Nanotecnologie
possono consentire
miniaturizzazione
e ottimizzazione di
dispositivi, di
membrane e di
nuovi biomateriali
La Microfluidica
deve permettere
l’integrazione
della
miniaturizzazione
elettronica con
quella idraulica

46. WEARABLE ARTIFICIAL KIDNEYS (WAK)
∼ 4.5Kg
filter, tubes,
electronic monitor
Implantable, like
a pace-maker?

47. ADDING LIFE TO YEARS
““TheThe qualityquality,, notnot thethe
longevitylongevity ofof oneone’s life,’s life,
isis whatwhat isis importantimportant””