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Policlinico S.Orsola-Malpighi
Bologna - ITALY
Azienda Ospedaliero-Universitaria
L’evoluzione della dialisi dagli anni 70 ad
oggi
Antonio Santoro
1854: The Scientific Basis for Dialysis1854: The Scientific Basis for Dialysis
Thomas GrahamThomas Graham
1805 1805 -- 18691869
“... “might be applied to medicine ...
1945: The First Surviving Patient (1)
Willem Kolff Kolff´s rotating drum dialyzer
(1943, Kampen, Netherlands)
Prevalence rates of end-stage kidney disease in
different countries
Jha V. et al. Lancet 2013
China South
AfricaIndia
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 terminal renal failure do not
receive treatment
IL RESTO
DEL MONDO
USA
20%
Global: 1,895,000 dialysis patients
1.200.000.000 5.800.000.000
abitanti47%EUROPA
17%
GIAPPONE
16%
abitanti abitanti
2,000
2,500
200
250
Dialyzers ('000 000)HD patients ('000)
Hemodialysis patients: Annual growth rate: 6%
World population: Annual growth rate: 1.1%
Annual need for dialyzers (in 2011): 222,000,000 filters
Today
0
1,000
0
100
1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
HD Patients
Dialyzers
Clinical cross-segmentation of dialysis population
Chronic comorbidities
Age 6
0+
Ath
ero
scle
rosis
Dia
bete
s
Hyperte
nsio
n
Card
iom
iopath
y
…E
PO
resis
tance
Ele
ctro
lyte
s
dis
ord
ers
Obesity
Cachexia
LVH
Dia
lysis
-rela
ted
com
plic
atio
ns
Hypotension � � � �
Hypertension � � � � � �
Arrhythmias � � � �
Macro inflammation � � � � �
:
Bleeding �
Amyloidosis � � �
PERCHE’ LA DIALISI SI E’ INNOVATA ?
Optimize the correction of the uremic status and preventing complications
Continuous growth of the prevalent population
8000
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
HR
QL
composite
sco
re
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
Essential elements in Hemodialysis
Water treatment system
Dialysis machine
Filter or dialyzer (membrane)Filter or dialyzer (membrane)
Blood lines
Needles
Catheters
Dialysis fluid
Blood
The membrane
Essential Requirement
Retention of bacterial contaminants
Essential Requirement
Low activation of blood components
High permeability for
low and middle MW uremic toxins
? Albumin Loss
Membrane cellulosiche
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
Bemberg factory at Wuppertal-Barmen
RugositàRugosità, , biocompatibilitàbiocompatibilità, , permeabilitàpermeabilità selettivaselettiva e e nanoporinanopori
Helixo
ne®®Fresenius
Polysulfone®®
Nanocontrolled Standard
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
membranemembrane
– Influenced by;
• Membrane chemistry [determines specificity]
• Membrane microstructure [determines capacity]
– Adsorption can occur both on the inner and outer surface
of the membrane
M. Hayama et al. Journal of Membrane Science
Fluorescence across hollow fibre wall showing the adsorption of labelled
endotoxin
Oxiris®
CH2
CH CCH2
CH3
SO3 Na-- --
+
N
NH
N
NH2
NHNH
- CH2
CN
Basis structure
(polyacrylonitrile)
N
NH
Polycation :
Polyethyleneimine
Endotoxin adsorption
(negatively charged)
oXiris: Endotoxin adsorption
Lipid A (active part of endotoxin)
Ionic binding
Endotoxin:
� high MW molecule (100 000 to 5MDaltons)
�chemical composition: polysaccharide, carbohydrate and lipid A
P
O
O
O
O
-
Ionic binding
with free amine
groups of PEI
** S. Morimoto et al, Polymer journal, vol.27, 8, 1995, 831
S. Mitzner et al, Artificial Organs, 17 (9), 1993, 775
HFR Hemo Filtrate
Reinfusion
Originalscheme
Quf
QR
QR = Quf
AdsorptionQbi
Convection
uf rigeneration and utilisation as infusion fluid
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
∆uf
Qdi
Qdo
Qbo
DialysateDiffusion
Elementi tecnici “fondamentali” delle nuove
macchine da dialisi
• Affidabilità e durata
• Accurato controllo dell’ultrafiltrazione e del bilancio
dei fluidi dei fluidi
• Preparazione del liquido di dialisi sterile,
biologicamente compatibile, e con composizione
controllata e modulabile
Evoluzione dei sistemi di controllo di UF
Camere di bilanciamento
Flussimetro a turbinettaFlussimetro a induzione
Morsetto
Flussimetro differenziale di massa di Coriolis
• Differenziale: accuratezza indipendente dal volume totale trattato
• Di massa: più immune a • 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
Pompe volumetriche ad alta
precisione
Sonda non invasiva
Accuratezza 0,1 mS/cm
Elemento fondamentale della dialisi è da sempre la soluzione
dializzante
�Elettroliticamente stabile e modulabile
�Contenente il tampone per EAB
Dalla “culla batterica” alla sterilità assoluta
�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
Acqua
MULTIPURE
Membrane
pla
sm
a c
on
c. (m
mo
l/l)
Qualitative trend of the patientbicarbonatemia and acetatemiaduring acetate dialysis
Acetate dialysis
blood dialysatedialysate
CHCH33COOCOO--
HCO3-
0 30 60 90 120 180 240
time (min)
pla
sm
a c
on
c. (m
mo
l/l)
[CH3COO-]
[HCO3-]
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
New Perspectives in Serum Electrolyte Control: Potassium
Profiling in Acetate-Free Biofiltration
Na+ 130 - 155 mEq/l
Ca++ 3.7 - 4.5 mEq/l
Mg++ 0.7 - 0.8 mEq/l
K+ 1.0 - 5.5 mEq/l
RANGES
VEN
Sodium Bicarbonate
Infusion Bag
Venous
Chamber
Infusion
Chamber
Buffer-Free
Concentrate Bag
(K=19 g/l)
ART
Buffer Free
Concentrate Bag
(K=0 g/l)
Pre-filter
Chamber
Arterial
Chamber
Twin-bag systemSantoro A. Contrib. Nephrol 2007
Il Il rapportorapporto medicomedico--computercomputer
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 purposesadministrative purposes
– Computerised monitoring of
dialysis parameters
– Computerised clinical records
– Modelling and simulation
– Computerised control of
dialysis equipment
AutomazioneAutomazione in in dialisidialisi
• L’automazione come informatizzazione
di dati clinici e dati macchina
• L’automazione come controllo di • L’automazione come controllo di
processi
• La automazione nella gestione della
terapia dialitica : I biofeedbacks
Networking and connectivity
PC03 PC02HUB
Local Network
Physician SERVER
Hospital Dialysis CentreRouter 1
Router 2
Limited Care Centre
PC01
Possibilità Attuali di
Monitoraggio della
Dialisi
• WHY ?
WHEN ?• WHEN ?
• HOW ?
…. and what kind of results ?
SENSORS IN DIALYSIS
Blood volume
monitoring
Blood
temperature
monitoring
Artificial
intelligence
PatientDialysis
machine
Artificial
intelligence
PatientDialysis
machine
INTRADIALYTIC MONITORING
• Solute removal (urea)
Na balance• Blood volume
RELATED
PARAMETERS
SPECIFIC
BIOCHEMICAL AND
HEMODYNAMICS
PARAMETERS
• Na balance
• K & Ca balance
• HCO3 balance
• H2O balance
(UF rate)
• A-V flow
• T° balance
• SO2
• 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 Mutivalent monitoring during HD
ECFVECFV
RR
elel
atat
iviv
ee
CC
hh
aa
nn
gg
ee
ss Thermal balanceThermal balance
BVBV
BPBP
Dialysis StartDialysis Start Dialysis stopDialysis stop
ss
UFRUFR
HRHR
SO2SO2
Heart rate
Blood Pressure
Alarm
logic
Blood volume
Alarm
logic
Heart rate
Continuous
Integrated
Alarm
logic
Blood
Volume
Blood
Pressure
Continuous
logic
modify
machine
action
Dialysis
Machine
Controller Dialyzer Patient
BV error
+-
Desired BV
UF set
DC set
UF
DCBV
Blood Volume Regulation During Hemodialysis,
Blood Volume
Monitor
Measured BV
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
Energy
Transfer Arterial T° control
AUTOMATIC T° CONTROL IN EXTRACORPOREAL CIRCUIT
PatientDialysisMachine
T° controller
Dialysate
T° controlVenous T°
Control
Frequency of hemodialysis treatments with symptomatic hypotension
for each 4-week phase with energy control (treatment A) or body
temperature control (treatment B).
8
10
12
14
No
. o
f tr
ea
tmen
ts w
ith
hyp
ote
nsio
n
38
T [°C]
Temperature control
treatment (B treatment)
0
2
4
6
8
Treatment A Treatment B
No
. o
f tr
ea
tmen
ts w
ith
hyp
ote
nsio
n
Maggiore Q. Pizzarelli F.Santoro A.et al. AJKD,2002
0.0 0.5 1.0 1.5 2.0
35
36
37
t[h]
Tven
Tbody
-100
0
0.0 0.5 1.0 1.5 2.0t[h]
E[kJ]
Pathways to Renal Replacement Therapy
Undiagnosed
Community
CKD
CKD or AKI in
Secondary Care
Conv. HD
Known
Community
CKD
Kidney
Care
Centre/Satellite
HD/HDF/HF
Home HD
PD
Conservative
Care
Late
Referral
Timely
Referral
AKI
Trasplant
Conv. HD
Nocturnal HD
Daily HD
6 times/week
HD (4 hrs.)
6 times/week
HD (8 hours)
3 times/wek 8
hours
Evolution of Hemodiafiltration Techniques
Soft convection
(≤ 3-6 L/session)
Biofiltration
Classic ( ≤9 L/session)
HDF
Hard Online HDFInternal HDF
pre-HDF post-HDF Pre/post-HDF
Mid-Dilution
AFB
Hard
(>15 liters exchanged)
PFD
Double high-flux HDF
PHF
HFR
Push-Pull HDF
Reference Study design Intervention Patient number Outcome HR 95% CI of HR
ESHOL RCT hfHD vs olHDF 906 improved survival in olHDF (by 30%) 0.70 0.53 – 0.92
2012 (5) 456 = olHDF
Turkish HDF study RCT hfHD vs olHDF 782 no difference in mortality 0.82 0.59 – 1.16
2012 (4) 391=olHDF
CONTRAST RCT lfHD vs olHDF 714 no difference in mortality 0.95 0.75 – 1.20
2012 (3) 358 = HDF
Locatelli et al. RCT HD vs HDF 146 no difference in mortality - -
2010 (10) &HF 36 = HF, 40 = HDF
Wizemann RCT HD vs HDF 44 no difference in mortality - -
2001 (9) 23 = HDF
Schiffl et al. cross-over hfHD vs olHDF 76 no difference in mortality - -
Studies describing the relation between HDF versus HD and mortality
Schiffl et al. cross-over hfHD vs olHDF 76 no difference in mortality - -
2007 (11)
DOPPS obs HD vs hfHD, 2165 improved survival in HDF (by 35%) 0.65 -
2006 (12) lfHDF & hfHDF 263 = HDF
EuCliD obs HD vs olHDF 2564 improved survival in olHDF (by 35.3%) 0.57 0.38 - 0.87
2006 (13) 394 = HDF
Bosch et al. obs HD vs HDF 183 improved survival in HDF (by 60%) 0.41 -
2006 (14) 25 = HDF
RISCAVID obs HD vs HDF 757 improved survival in HDF (by 22%) - -
2008 (15) 303 = HDF 129 olHDF, 204 HDF with bags
Vilar et al. obs HD vs HDF 858 improved survival in HDF (by 34%) 0.45 0.35 - 0.59
2009 (16) 232 = HDF
Kaplan–Meier curves for 36-month survival in the intention-to-
treat population (P=0.01 by the log-rank test). HD, hemodialysis
OL-HDF
HD
1.0
0.8
0.6
Su
rviv
al
Pro
ba
bilit
y
J Am Soc Nephrol 24: 487–497, 2013
Log-rank p-value:0.01
0.4
0.2
0.0
Su
rviv
al
Pro
ba
bilit
y
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
I pazienti con MRC che I pazienti con MRC che
arrivano alla dialisi arrivano alla dialisi
sono in aumento, sono sono in aumento, sono
per la maggior parte per la maggior parte
anziani e ciascuno è anziani e ciascuno è
Ed il futuro………………………………..
anziani e ciascuno è anziani e ciascuno è
differente dall’altro per differente dall’altro per
profilo clinico e profilo clinico e
comorbiditàcomorbidità
E’ possibile pensare di offrire una unica e standardizzata terapia dialitica che risponda alle necessità di ognuno di loro ?
Ed il futuro………………………………..
Efficacia
• Personalizzazione
della terapia
Semplificazione:
� Prescrizione standardizzata
Variabilità dei pazienti: efficacia vs. semplificazione
della terapia
• Elevato numero di
opzioni disponibili
standardizzata
� “Regole cliniche universali”
Popolazione in dialisi
vs.
% con benefici clinici