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Policlinico S.Orsola-Malpighi
Azienda Ospedaliero-Universitaria
Bologna - ITALY
L’evoluzione della dialisi dagli anni 70 ad
oggi
Antonio Santoro
1854: The Scientific Basis for Dialysis
Thomas Graham
1805 - 1869
“... “
might be applied to medicine ...
1945: The First Surviving Patient (1)
Willem Kolff
Kolff´s rotating drum dialyzer
(1943, Kampen, Netherlands)
ESRD Patients
HD
PD
Tx
World Population
2,456,000
1,692,000
203,000
561,000
6,8 billion
Annual Growth Rates
ESRD
HD
PD
6-7%
6-7%
6-7%
Crescita 1,1%
Annual incidence of end-stage kidney disease in diff
erent countries
Jha V. et al. Lancet 2013
Prevalence rates of end-stage kidney disease in
different countries
China
South
Africa
India
Jha V. et al. Lancet 2013
The lower global average of
360 p.m.p. suggests that,
from the global perspective,
access to treatment is still
limited in many countries and
a number of patients with
terminal renal failure do not
receive treatment
Global: 1,895,000 dialysis patients
USA
20%
1.200.000.000
abitanti
IL RESTO
DEL MONDO
47%
EUROPA
17%
GIAPPONE
16%
5.800.000.000
abitanti
PD
11%
HD
89%
Global: 1,895,000 dialysis patients
Global: 203,000 PD patients
USA
13%
EU
13%
Other
68%
Japan
12%
Today
Hemodialysis patients:
Annual growth rate: 6%
World population:
Annual growth rate: 1.1%
Annual need for dialyzers (in 2011): 222,000,000 filters
Dialyzers ('000 000)
HD patients ('000)
2,500
250
2,000
200
1,000
100
Dialyzers
HD Patients
0
1970
0
1975
1980
1985
1990
1995
2000
2005
2010
2015
Clinical cross-segmentation of dialysis population
Chronic comorbidities
Cachexia
Macro inflammation
Obesity
Electrolytes
disorders
Arrhythmias
…
EPO resistance
Cardiomiopathy
Dialysis-related
complications
Hypertension
Hypertension
Hypotension
Diabetes
Atherosclerosis
Age 60+
LVH
:
Bleeding
Amyloidosis
PERCHE’ LA DIALISI SI E’ INNOVATA ?
Continuous growth of the
prevalent population
Optimize the correction of the
uremic status and preventing
complications
8000
7000
Inadequate number of transplants /
long waiting time
kidney
5000
4000
3000
liver
2000
heart
Reduce the
unphysiology of
dialysis
1000
0
2003
2004
Mental health composite
HRQL composite score
6000
Physical health composite
60
50
40
30
20
10
2005
0
Mean time on waiting list: 3.1 yrs
0-2
3-4
5-6
7-8
9-10
Number of moderate or severe ESAS symptoms
Death rate on waiting list 1.29%
(Centro Nazionale Trapianti,2006)
IMPROVE SURVIVAL
Improve the quality of life
Essential elements in Hemodialysis
Water treatment system
Dialysis machine
Filter or dialyzer (membrane)
Blood lines
Needles
Catheters
Innovation in hemodialysis
Membranes
Machines
Techniques
The membrane
Dialysis fluid
Blood
Essential Requirement
Essential Requirement
Retention of bacterial contaminants
Low activation of blood components
High permeability for
low and middle MW uremic toxins
? Albumin Loss
Membrane cellulosiche
Bemberg factory at Wuppertal-Barmen
Una specifica varietà per dialisi viene prodotta in
Europa a partire el 1965 nella fabbrica Bemberg e
viene commercializzata con il nome di Bemberg
Cuprofan
When used in non disposable dialysers it
was a labour intensive activity
From Macrodevices to ………
Device miniaturization
Membranes based on synthetic polymers
La porosità della membrana
Rugosità,, biocompatibilità
Rugosità
biocompatibilità,, permeabilità selettiva e nanopori
Nanocontrolled
Helixo
ne®
Standard
Fresenius
Polysulfone®
Adsorption
– Adsorption can occur at the membrane surface when the
molecule can not pass through the membrane.
– Adsorption can occur within the membrane matrix ( Bulk
adsorption ) when the molecules can permeate the
membrane
– Influenced by;
• Membrane chemistry [determines specificity]
• Membrane microstructure [determines capacity]
– Adsorption can occur both on the inner and outer surface
of the membrane
Dialysis membranes
Blood side
Dialysate side
Radiolabeled beta2-MG and scintigraphic analysis
Fluorescence across hollow fibre wall showing the adsorption of labelled
endotoxin
M. Hayama et al. Journal of Membrane Science
Oxiris®
NH
NH
CH3
- CH
-
CH2
CN
CH2
- C
SO3 Na
N
+ NH2
NH
N
CH2
NH
Basis structure
(polyacrylonitrile)
Polycation :
Polyethyleneimine
Endotoxin adsorption
(negatively charged)
oXiris: Endotoxin adsorption
Endotoxin:
high MW molecule (100 000 to 5MDaltons)
chemical composition: polysaccharide, carbohydrate and lipid A
Lipid A (active part of endotoxin)
O
O
P
O
** S. Morimoto et al, Polymer journal, vol.27, 8, 1995, 831
S. Mitzner et al, Artificial Organs, 17 (9), 1993, 775
O
Ionic binding
with free amine
groups of PEI
HFR
Hemo Filtrate
Reinfusion
Original
scheme
Qbi
Adsorption
Quf
Convection
QR
QR = Quf
uf rigeneration and
utilisation as
infusion fluid
Qdo
Diffusion
Dialysate
Qdi
Ghezzi PM et al. Use of the ultrafiltrate
obtained in two-chamber
hemodiafiltration as replacement fluid
Int J Artif Organs 1991; 14 (6): 227-34
Qbo
∆uf
Evoluzione macchine per dialisi
Elementi tecnici “fondamentali” delle nuove
macchine da dialisi
• Affidabilità e durata
• Accurato controllo dell’ultrafiltrazione e del bilancio
dei fluidi
• Preparazione del liquido di dialisi sterile,
biologicamente compatibile, e con composizione
controllata e modulabile
Evoluzione dei sistemi di controllo di UF
Morsetto
Camere di bilanciamento
Flussimetro a turbinetta
Flussimetro a induzione
Flussimetro differenziale di massa di Coriolis
• Differenziale: accuratezza
indipendente dal volume totale
trattato
• Di massa: più immune a
presenza di aria
• A flusso continuo: tempo di
funzionamento coincidente con
il tempo effettivo di dialisi
• Sanitary design
Il sistema di preparazione
• Pompe volumetriche per il concentrato, molto accurate grazie al controllo
conducimetrico ad anello chiuso
Induced
current
Sonda non invasiva
Pompe volumetriche ad alta
precisione
Accuratezza 0,1 mS/cm
Dalla “culla batterica” alla sterilità assoluta
Elemento fondamentale della dialisi è da sempre la soluzione
dializzante
Elettroliticamente stabile e modulabile
Contenente il tampone per EAB
Priva di tossine
…. possibilmente non contaminata
La preparazione manuale della soluzione costituiva una
vera e propria “culla batterica” oltre ad avere una
composizione imprecisa e non modulabile
Accurati sistemi di filtraggio dopo la preparazione
assicurano la sterilità dei liquidi di dialisi
Soluzione dializzante
Soluzione+ d’infusione
Preparazione
dialisato
MULTIPURE
Acqua
Acetate dialysis
blood
dialysate
HCO3CH3COO-
plasma conc. (mmol/l)
Membrane
Qualitative trend of the patient
bicarbonatemia and acetatemia
during acetate dialysis
[C H 3C OO-]
[H C O3-]
0
30
60
90
1 20
time (min )
1 80
24 0
Biofiltration (BF): preliminary observations
•
•
•
Ultrashort hemodiafiltration (3h)
3 liters of NaHCO3 substitution fluid
5 clinically stable HD patients on CH
switched to BF
• 6 months follow-up
Benefits:
Less symptomatic hypotension during
BF
Metabolic acidosis and nutritional
status improved in BF
P. Zucchelli, A. Santoro, J Nephrol 1984
Acetate-Free Biofiltration in the 80s
New Perspectives in Serum Electrolyte Control: Potassium
Profiling in Acetate-Free Biofiltration
RANGES
Sodium Bicarbonate
Infusion Bag
Buffer-Free
Concentrate Bag
(K=19 g/l)
Venous
Chamber
VEN
Infusion
Chamber
Pre-filter
Chamber
Na+
Ca++
Mg++
130 - 155 mEq/l
3.7 - 4.5 mEq/l
0.7 - 0.8 mEq/l
K+
1.0 - 5.5 mEq/l
Arterial
Chamber
ART
Buffer Free
Concentrate Bag
(K=0 g/l)
Twin-bag system
Santoro A. Contrib. Nephrol 2007
Citrasate: cardiovascular stability.
Il rapporto medico
medico--computer
Possibili usi del Personal Computer in una divisione di nefrologia e dialisi.
Santoro A. et. Al.
Attualità nefrologiche e dialitiche San Carlo 1984
– Patient archiving for
administrative purposes
– Computerised monitoring of
dialysis parameters
– Computerised clinical records
– Modelling and simulation
– Computerised control of
dialysis equipment
Automazione in dialisi
• L’automazione come informatizzazione
di dati clinici e dati macchina
• L’automazione come controllo di
processi
• La automazione nella gestione della
terapia dialitica : I biofeedbacks
Networking and connectivity
Local Network
PC03
PC02
HUB
Physician
SERVER
Hospital Dialysis Centre
Router 1
Limited Care Centre
PC01
Router 2
Possibilità Attuali di
Monitoraggio della
Dialisi
• WHY ?
• WHEN ?
• HOW ?
…. and what kind of results ?
SENSORS IN DIALYSIS
Blood volume
monitoring
Blood
temperature
monitoring
Dialysis
machine
Patient
Artificial
intelligence
INTRADIALYTIC MONITORING
RELATED
PARAMETERS
Solute removal (urea)
Na balance
K & Ca balance
HCO3 balance
H2O balance
(UF rate)
• A-V flow
• T° balance
• SO2
•
•
•
•
•
SPECIFIC
BIOCHEMICAL AND
HEMODYNAMICS
PARAMETERS
Blood volume
KT/V
Heart rate
Blood pressure
Cardiac output
Arterial resistances
Venous tone and
capacitance
• ECG signal
• Gas & AB balance
•
•
•
•
•
•
•
Mutivalent monitoring during HD
BP
R
el
at
iv
e
C
h
a
n
g
e
s
BV
ECFV
Thermal balance
SO2
HR
UFR
Dialysis Start
Dialysis stop
DIALYSIS SESSION WITH ACUTE HYPOTENSION
Profiled variables
Weigth loss rate
Sodium
Bicarbonate
Potassium
Calcium
Combinations of dialysate sodium and ultrafiltration profiles
Blood Pressure
Alarm
logic
Blood volume
Alarm
logic
Heart rate
Integrated
Alarm
logic
Heart rate
Continuous
logic
Blood
Volume
modify
machine
action
Blood
Pressure
Dialysis
Machine
Blood Volume Regulation During Hemodialysis,
Desired BV
+
UF set
DC set
BV error
Controller
UF
DC
Dialyzer
BV
Patient
-
Measured BV
Blood Volume
Monitor
A. Santoro et al, Am J Kidney Dis, 1998, 32, 5: 738-748
Biofeedback HD versus conventional HD with constant dialysate conductivity and
ultrafiltration rate; outcome: IDH.
Absolute treatment effect estimate (rate difference).
Nephrol Dial Transplant 2013;28:182–191
AUTOMATIC T° CONTROL IN EXTRACORPOREAL CIRCUIT
Energy
Transfer
Arterial T° control
Dialysis
Machine
T° controller
Patient
Venous T°
Control
Dialysate
T° control
Temperature control
treatment (B treatment)
T [°C]
38
37
Tbody
36
Tven
35
0.0
0.5
1.0
1.5
2.0
t[h]
E[kJ]
No. of treatments with
hypotension
Frequency of hemodialysis treatments with symptomatic hypotension
for each 4-week phase with energy control (treatment A) or body
temperature control (treatment B).
14
12
10
8
6
4
2
0
Treatment A
0
-100
0.0
0.5
1.0
1.5
2.0
t[h]
Maggiore Q. Pizzarelli F.Santoro A.et al. AJKD,2002
Treatment B
Pathways to Renal Replacement Therapy
CKD or AKI in
Secondary Care
Undiagnosed
Community
CKD
Centre/Satellite
HD/HDF/HF
Late
Referral
Known
Community
CKD
AKI
Timely
Referral
Conv. HD
Nocturnal HD
Daily HD
Kidney
Care
Home HD
PD
Conservative
Care
Trasplant
6 times/week
HD (4 hrs.)
6 times/week
HD (8 hours)
3 times/wek 8
hours
Evolution of Hemodiafiltration Techniques
Soft convection
HDF
Classic ( ≤9 L/session)
(≤ 3-6 L/session)
Biofiltration
Internal HDF
Hard
pre-HDF
post-HDF
Online HDF
Pre/post-HDF
Mid-Dilution
(>15 liters exchanged)
AFB
PFD
Push-Pull HDF
Double high-flux HDF
HFR
PHF
Studies describing the relation between HDF versus HD and mortality
Reference
ESHOL
Study design
Intervention
Patient number
Outcome
HR
95% CI of HR
RCT
hfHD vs olHDF
906
improved survival in olHDF (by 30%)
0.70
0.53 – 0.92
no difference in mortality
0.82
0.59 – 1.16
no difference in mortality
0.95
0.75 – 1.20
no difference in mortality
-
-
no difference in mortality
-
-
2012 (5)
Turkish HDF study
456 = olHDF
RCT
hfHD vs olHDF
2012 (4)
CONTRAST
391=olHDF
RCT
lfHD vs olHDF
2012 (3)
Locatelli et al.
RCT
RCT
HD vs HDF
146
&HF
36 = HF, 40 = HDF
HD vs HDF
44
2001 (9)
Schiffl et al.
714
358 = HDF
2010 (10)
Wizemann
782
23 = HDF
cross-over
hfHD vs olHDF
76
no difference in mortality
-
-
obs
HD vs hfHD,
2165
improved survival in HDF (by 35%)
0.65
-
lfHDF & hfHDF
263 = HDF
HD vs olHDF
2564
improved survival in olHDF (by 35.3%)
0.57
0.38 - 0.87
improved survival in HDF (by 60%)
0.41
-
757
improved survival in HDF (by 22%)
-
-
303 = HDF
129 olHDF, 204 HDF with bags
858
improved survival in HDF (by 34%)
0.45
0.35 - 0.59
2007 (11)
DOPPS
2006 (12)
EuCliD
obs
2006 (13)
Bosch et al.
394 = HDF
obs
HD vs HDF
2006 (14)
RISCAVID
25 = HDF
obs
HD vs HDF
2008 (15)
Vilar et al.
2009 (16)
183
obs
HD vs HDF
232 = HDF
J Am Soc Nephrol 24: 487–497, 2013
Kaplan–Meier curves for 36-month survival in the intention-totreat population (P=0.01 by the log-rank test). HD, hemodialysis
1.0
Survival Probability
OL-HDF
0.8
HD
0.6
0.4
Log-rank p-value:0.01
0.2
0.0
0
6
12
18
24
30
36
Follow-up (months)
HD
450
388
327
275
235
196
165
OL-HDF
456
367
318
284
232
200
179
J Am Soc Nephrol 24: 487–497, 2013
Ed il futuro………………………………..
I pazienti con MRC che
arrivano alla dialisi
sono in aumento, sono
per la maggior parte
anziani e ciascuno è
differente dall’altro per
profilo clinico e
comorbidità
E’ possibile pensare di offrire una unica e
standardizzata terapia dialitica che risponda
alle necessità di ognuno di loro ?
Ed il futuro………………………………..
Variabilità dei pazienti: efficacia vs. semplificazione
Efficacia
• Personalizzazione
della terapia
• Elevato numero di
opzioni disponibili
Semplificazione:
Prescrizione
standardizzata
“Regole cliniche
universali”
Popolazione in dialisi
vs.
% con benefici clinici