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)

ESRD Patients 2,456,000

HD 1,692,000

PD 203,000

Tx 561,000Tx 561,000

World Population 6,8 billion

Annual Growth Rates

ESRD 6-7%

HD 6-7%

PD 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

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

PD

11%

HD

89%

Global: 1,895,000 dialysis patients

Other

USA

13%

EU

13%

Global: 203,000 PD patients

Other

68%Japan

12%

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

Innovation in hemodialysis

Membranes

MachinesMachines

Techniques

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

When used in non disposable dialysers it

was a labour intensive activity

From From MacrodevicesMacrodevices to ………to ………

Device Device miniaturizationminiaturization

Membranes based on synthetic polymers

La porosità della membranaLa porosità della membrana

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

Dialysis membranes

Radiolabeled beta2-MG and scintigraphic analysisBlood side

Dialysate side

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

Evoluzione macchine per dialisi

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

Acetate-Free Biofiltration in the 80s

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

Citrasate: cardiovascular stability.

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

DIALYSIS SESSION WITH ACUTE HYPOTENSION

Profiled variables

Weigth loss rate

SodiumSodium

Bicarbonate

Potassium

Calcium

Combinations of dialysate sodium and ultrafiltration profiles

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

J Am Soc Nephrol 24: 487–497, 2013

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