Personalizzazione della terapia: vantaggi e sfide legate all’unicità

del paziente in emodialisi Antonio Santoro

U.O. di Nefrologia, Dialisi ed Ipertensione Policlinico S.Orsola-Malpighi

Bologna - ITALY

Azienda Ospedaliero-Universitaria

Comparison between General Mortality and Dialysis Mortality

Country Death rates per 100 patient years

General population age 55-69 y

HD population age 55-69 y

Ratio of HD to general population

Australia 0.83 16.1 19.4

Belgium 1.10 21.3 19.4

Canada 0.97 16.1 16.6

France 1.01 13.7 13.6

Germany 1.13 15.6 13.8

Italy 0.97 11.4 11.8

Japan 0.82 5.2 6.3

New Zealand 1.02 16.2 15.9

Spain 0.98 15.7 16.0

Sweden 0.85 18.7 22.0

United Kingdom 1.16 16.5 14.2

United States 1.22 19.0 15.6

Ref: Dor et al, Int J Health Care Finance Econ. 2007

Advance Access published November 22, 2010

Clinical cross-segmentation of dialysis population

Chronic comorbidities Age 65+ Atherosclerosis

Diabetes

Hypertension

Cardiom

iopathy

…

EPO resistance

Electrolytes disorders O

besity

Cachexia

Dialysis-related

complications

Hypotension Hypertension

Cardiac arrhythmias Micro/Macro inflammation

: Bleeding

Amyloidosis

LVH

5

HD patients comorbidities stratification

© 2008, Gambro 5

ESRD patients/dialysis

Diabetes (type II) 25-55%

CV risk (atherosclerosis, PAD)

>55%

Chronic inflammation

> 50%

Arrhythmias > 20%

At bleeding risk due to medication with

oral anticoagulant 20%

At high bleeding risk

5-8 %

ESRD patients are a lot, old and different from each other…

Is it possible to offer a unique, standard dialysis to fulfill all patients’ needs?

DIALYSIS INNOVATIONS 1990-2014

Monitoring/controlling systems blood volume, blood temp,

electrolytes, profiling, biofeedback, efficiency…

Variable schedules short daily,

nocturnal, more than 3…

New membranes membrane pore size,

fiber diameter, chemical composition

surface treatment nanotechnology

Different modalities HFHD-HDF-HF

Water / Dialysate on-line preparation

microbiol quality

Plasma Volume

Blood Pressure

Baroreflex Response

Vasoconstriction Heart Rate

Cardiac Contractility HRV

Blood Pressure

Change in pH and electrolyte concentration

ULTRAFILTRATION DIFFUSION

Ref. Zucchelli / Santoro Blood Purif 1993

Mean UF rate = 0.875 L/h

1.0 0

0

-6

-12

-18

-24 0 60 120 180 240

% change in blood volume

Total Ultrafiltrate (L)

Time , min

Patient 1

2 3 4 5

3.0 2.0

1.5 1.0 0.5 0

UF rate L/h

Hyd

rost

atic

Pre

ssur

e

Proteins Solutes (<50.000 D)

Edema Blood Filter Ultrafiltrate

Ultrafiltration “Plasma Refilling”

MECHANISMS WHICH CAN AFFECT PLASMA REFILLING DURING DIALYSIS

1. Impairment of peripheral vasoconstriction during volume removal

2. Increase in hydrostatic capillary pressure

3. Depletion of interstitial volume

4. Oncotic pressure changes

• Acetate • Release of cytokines (IL1-TNF-IL6) • Autonomic neuropathy • Thermal stress

• Compromised cardiac function • Peripheral pooling of blood volume

• Low dialysate sodium concentration • High transcellular urea gradient • High UF or Dry body weight error

• Hypoalbuminemia • Alteration in interstitial fluid drainage and lymph flow

“Can Advances in Hemodialysis Machine Technology Prevent Intradialytic Hypotension?”

Cartoon depicting a number of different ultrafiltration profiles

Davenport A. Semin Dial (2009); 22: 231-236

13

Clinical significance of Monitoring the Blood Volume variations

1

3

5

7

9

11

13

15

17

2

1.8

1.6

1.4

1.2

1

0.8

0.6

0.4

0.2

0.0 0 40 80 120 160 200 240

Blo

od v

olum

e ch

ange

(%)

Wei

ght l

oss

rate

(Kg/

h)

Time (min)

Assesment of plasma refilling rate

“The use of dynamic tests, based on ultrafiltration “pulses”, seems promising towards optimising the patient’s dry-weight and the individually evaluation of the capillary filtration coefficient.”

Santoro et al, Int. J. Art. Org, 1997.

Combinations of dialysate sodium and ultrafiltration profiles

Controller Dialyzer

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

Patient

BV %

Blood volume control in action

Effects of blood volume control on BV behaviour

Systolic arterial pressure in standard and biofeedback hemodialysis

SAP

chan

ges

(%)

30 60 90 120 150 180 210

Time (min)

* p<0.05 B vs A

* * *

0

-4

-8

-12

-16

-20

-24

-28

Effects of automatic blood volume control over intradialytic hemodynamic stability, E. Mancini et al, Int, J. Art. Org., 1995, 18, 9: 495-498

Standard HD

Biofeedback HD

Dialysis-related symptomatic hypotension

Santoro A. et al, Blood volume controlled hemodialysis in hypotension-prone patients: A randomized, multicenter controlled trial. Kidney Int. 2002, 62, 1034-1045

02468

1012

Ave

rage

N°.

of

colla

pses

< 5 5 ÷ 8 > 8

Patient Class based on hypotension episodes per

month

Conventional HDBV-controlled HD

P <0.01

P < 0.005

Biofeedback HD versus conventional HD with constant dialysate conductivity and ultrafiltration rate; outcome: IDH. Relative treatment effect estimate (rate ratio).

Nephrol Dial Transplant 201 3;28:1 82–1 91

Systematic review

Selby NN, McIntyre CW, AJKD 2006

Conventional HD

Blood volume Biofeedback

HD

BV controlled HD and Myocardial Stunning

ventricular wall motion abnormalities

HEM

OD

IALY

SIS

Bioincompatibily

Negative cardiovascular effects of Dialysis in frai patient

Diffusion Changes in pH, HCO3

and electrolytes

- - - - - - - - - - - - - - - - - - - - - - - - - -

During hemodialysis

DIALYSATE

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + +

Cellular membrane

Membrane

K+

Ca++

Ca++ K+

- - - + +

+ + + + + + + + + + + + + + + + + +

+ + + + -

+ + + + K+

PO4----

PO4----

HCO3-

PO4----

H+ +HCO3-

CO2

H2O + +

Ca++ H+

Na+

Action Potential and Transmemrane Ion Fluxes

0

1 2 Ca2+

3 K+

4 K+, Na+ 4

Na+

K+, Cl-

depolarization

Early repolarization

plateau repolarization

Rest potential

-100

-50

+50

0

A.M. Katz, Physiology of the heart, 3rd ed., 2000

Electrolyte disorders are one of the main HD-related factors that can cause QT interval alterations and cardiac arrhythmias.

Genovesi Nephr Dial Transp 2009

Genovesi Europace 2008

QT msec mmol/L

Effect of dialysis on arrhythmias

Time (min)

Pre - dialysis Dialysis

Ventricular Ectopic Beats before and during dialysis

Gaggi R. Santoro A. et al, Proceed ERA EDTA Lisbon, 2003

Acetate Free Biofiltration potassium profiled

Na+ = 145 -167 Cl- = 0 - 25 HCO3- = 120 – 167 Compositon in mEq/L

Qinf

Quf

No buffer in the dialysis fluid Acid base balance physiologically restored by infusion of a sterile solution of

sodium bicarbonate

Na+ = 130 -165 Cl- = 98 – 125 Ca2+ = 2,50 - 4 Mg2+ = 0,75 – 1,25 K+ = 0

Na+ = 130 -165 Cl- = 98 – 125 Ca2+ = 2,50 - 4 Mg2+ = 0,75 – 1,25 K+ = 7,2

In AFBK three electrolytes can be personalized and modulated during dialysis

Na+ (by dialysis fluid) HCO3

- (by Qinf adjustment) K+ (by dialysis profile)

-0,6

-0,4

-0,2

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Time (hours)

Log1

0(PV

C+1

)

Dialysis

KCONST KPROF Difference

Santoro A et al. Nephrology Dialysis & Transplantation , 2008

Differences in ventricular ectopic beats appearance

Calcium and potassium changes during haemodialysis alter ventricular repolarization duration:

in vivo and in silico analysis

Scatter plot and regression line showing the significant inverse correlation between QTc interval duration and serum Ca2+ concentration changes during HD sessions (35 patients, 70 sessions).

Severi S.Santoro A. Nephrol Dial Transplant (2007) doi: 10.1093/ndt/gfm765

Calcium profiling in hemodiafiltration: a new way to reduce the calcium overload risk withou compromising cardiovascular stability Stefano Severi … Antonio Santoro

Int J Artif Organs. 2014 Apr 15;37(3):206-14. doi: 10.5301/ijao.5000320. Epub 2014 Apr 4

Calcium profiling in hemodiafiltration: a new opportunity to reduce the calcium overload risk in high calcium dialysis without

compromising cardiovascular stability. Short title: Dialysate calcium profiling

Stefano Severi, …… Antonio Santoro

SAP

DAP

32

Majority of ESRD patients suffers from chronic inflammation

CRP

33

Wanner et al, KI 2002

Majority of ESRD patients suffers from chronic inflammation: impact on CV complications

Elements for the realization of a low-inflammatory-impact dialysis treatment. Because of the multifactorial nature of inflammation in the chronic hemodialysis patient, an approach on several fronts should be implemented: on the one hand, the elimination of the factors inducing an inflammatory response, and on the other, the direct removal of the inflammatory mediators. Among the former, a high-quality water treatment system, the exclusive use of ultrapure dialysis fluids, and the avoidance of acetate in dialysate, as well as the use of highly biocompatible materials, are the main steps. Among the latter, apart from the mandatory use of high-flux membranes, adsorptive membrane, as well as the direct adsorption of inflammatory mediators on the sorbent cartridge, to arrive at the high-volume convection associated or not to diffusion are

the different possible options.

Kidney International (2014) 86, 235–237; doi:10.1038/ki.2014.81 Is hemodiafiltration the technical solution to chronic inflammation

affecting hemodialysis patients? Antonio Santoro and Elena Mancini

Panichi V et al. Nephrol. Dial. Transplant. 2008;23:2337-2343 Follow up (months)

CV

Cum

ulat

ive

Surv

ival

Chronic inflammation and mortality in HD: Effect of different dialysis modalities. Results from the RISCAVID study

This study showed the synergic effect of CRP and pro-inflammatory cytokines as the strong predictors of all-cause and cardio-vascular mortality. HDF was associated with an improved cumulative survival.

Time (months)

Cum

ulat

ive

surv

ival

%

0 5 10 15 20 25 30 35 40

1.0

0.9

0.8

0.7

0.6

0.5

Hemofiltration

Hemodialysis

Effect of on-line hemofiltration versus low-flux hemodialysis on mortality: A small randomized controlled trial

Santoro A et al Am J Kidney Dis 52:507-518,2008

n=32

n=32

The importance of High Convective Volume in HDF online

Ira M. Mostovaya Seminars in Dialysis 2014

Which patient can improve survival by HDF online?

The subgroups obtaining the greatest benefit were: • older,

• had no diabetes,

• dialyzed through an FAV

• higher Charlson comorbidity index.

Maduell JASN 2013

N=906

Biofeedback applied to maximize the convective volume on HDF online

Teatini et al. Blood Pur 2011

• UltraControl is a biofeedback system that automatically adjusts the actuator (UF rate) to keep hourly the TMP constant at a set value. As a closed-loop control system, this is insensitive to external influences such as the changing operative conditions of the dialyzer-patient system and does not require any external maneuver to compensate them.

• Moreover, the dialysis monitor automatically finds the TMP set point by a second biofeedback loop called ‘TMP scan’.

Comparison between standard infusion mode and pressure mode

Teatini et al. Blood Pur 2011 V. Panichi IJAO 2012

0

5

10

15

20

25

30

Volume Control Pressure Control

Con

vect

ive

Volu

me

(L)

0

5

10

15

20

25

30

Volume Control Pressure Control

Con

vect

ive

Volu

me

(L)

N=30 N=12

Hemorrhagic patient

Side effect of Heparin Heparin is also associated with a range of acute and chronic adverse

events that, given its widespread use, can be quite common1,2–5 and may further aggravate existing patient comorbidities:

- Osteoporosis (common)1,3 - Thrombocytopenia (common and potentially severe. Further

complicated by the advent of thrombosis)1,3,4

- Eosinophilia1 - Changes in lipid profile4,5

- Skin reactions1 - Hyperkalaemia1,2

- Hypoaldosteronism1

- Metabolic abnormalities1

© 2008, Gambro 42

1. Bick R and Frenkel E. Clin Appl Thromb Hemost. 1999;5(Suppl 1):S7–S15 2. Gheno G et al., Ann Ital Med Int 2002;17(1):51–53 3. Sonawane S et al., Semin Dial. 2006;19(4):305–10 4. Näsström B et al., BMC Nephrol. 2004;5:17–27 5. Näsström B et al., Nephrol Dial Transplant 2005;20(6):1172–1179

Citrate as anticoagulant

Thrombocyte

True Clotting

Ca2+ Ca2+

Ca2+

Ca2+

Ca2+

Heparin

• Citrate acts by binding calcium

• Citrate acts early in the cascade

• Citrate acts at several steps in the cascade

Citrate in dialysis fluid reduces thrombogenicity

Grundström et al. BMC Nephrology 2013, 14:216

• Randomized, controlled, prospective, cross-over

• 24 patients – 6 + 6 weeks with 8 treatments wash-out – 1 mM Citrate vs. 3 mM Acetate

• Citrate reduced intradialytic thrombogenecity – Increase in aPT-time over dialysis

– Reduced clotting in arterial air chamber

*

0

1

2

3

Arterial Chamber Venous Chamber

Rel

ativ

e C

lotti

ng S

core

Citrate Control

*

DIALYSIS INNOVATIONS 1990-2014

New membranes membrane pore size,

fiber diameter, chemical composition

surface treatment nanotechnology

Monitoring/controlling systems blood volume, blood temp,

electrolytes, profiling, biofeedback, efficiency…

Variable schedules short daily,

nocturnal, more than 3…

Water / Dialysate on-line preparation

microbiol quality

Different modalities HFHD-HDF-HF

CH2 CH C

-

CH2

CH2

CH3

CN

SO3 Na - - - - + N

NH

N

NH2

NH NH

Polyethyleneimyn (“ST”) Heparin ~ 3000 UI/m²

AN69

Available Active sites

reducing thrombogenicity

Heparin grafting results from an original and patented «multipoint ionic functionalization» process (via PEI):

Membrane saturation with heparin and stability of grafted heparin (no heparin release from the membrane)

: membrane grafting process

Heparin grafted membrane as a new standard for heparin-free treatment

M. Laville J Am Soc Nephrol 24: 2013: 4B, SA-PO1084

N=265

HD con flashing o HDF pre

Dialysis has moved from being a sort of halfway house technology to being a fully-fledged contributor to the therapeutic toolbox of nephrologists treating end-stage renal failure.