u.o. di nefrologia, dialisi ed ipertensione policlinico...
TRANSCRIPT
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.