Upload
others
View
18
Download
0
Embed Size (px)
Citation preview
Membrane dialitiche emergenti: prospettive nel paziente acuto
Elena Mancini
Nefrologia, Dialisi, Ipertensione Policlinico S.Orsola-Malpighi
Bologna - ITALY
Corso di Aggiornamento
“Acute kidney Injury: attualità e controversie”
Roma, 19-20 maggio 2011
Dialysis membranes in the chronic dialysis patients
Locatelli F. et al. J Am Soc Nephrol 2009
Patients with serum albumin < 4 g/dl
High flux membrane Low flux membrane
0 12 24 36 48 60 72 84
Months
Surv
ival
pro
babi
lity
of p
atie
nts
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
MPO study
Log Rank test: p=0.032
AKI and dialysis membranes Membrane-related aspects affecting the
course of dialysis-dependent AKI? bio-compatibility, efficiency
The actual knowledge about the effect of the
dialysis membrane on the AKI outcome (renal function recovery, patient survival)
The blood membrane interaction
Blood loses the protective effects of the endothelium
Complement Leukocyte Coagulation
MEMBRANE BIOCOMPATIBILITY
DIALYSIS MEMBRANES – BIOCOMPATIBILITY
Unsubstituted cellulose bioincompatible
Substituted/modified cellulose
more biocompatible
Synthetic membranes biocompatible
Cuprophan® LF Cellulose (di-)acetate LF, triacetate LF, HF, SF
AN69® HF. AN69® ST HF
Cuprammonium-rayon LF Hemophan® LF Polysulfone
Saponified cellulose ester (SCE) LF
SMC® LF Fresenius Polysulfon® PS400/600 LF/HF,
Cuprammonium-rayon polyethylene
Helixone® HF
Glycol Lf, MF, HF α- Polysulfone LF,HF,
Excebrane® LF APS HF, SF
VitabranE® HF,
Toraysulfone HF, SF
Polyethersulfone
DIAPES® LF, MF,HF,SF
PUREMA® LF, HF, SF
Polyamix® LF, HF,
Arylane® HF
Polyester-Polymer-Alloy (PEPA) HF, SF
PES alpha HF
LF, low-flux; MF, mid-flux; HF, high-flux; SF, super-flux
Polymethylmethacrylate LF, MF, HF, SF
Ethylene vinyl-alcohol (EVAL) LF
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Cellulosic membr Synthetic membr
Biocompatibility
Performance (hydraulic permeability, sieving coefficient)
World diffusion of synthetic membranes
HEMOcompatibility Burst of oxygen free radicals Oxidative stress Cytokines & Leukotrienes Protein and lipid peroxidation Endothelial cells activation
Protein cake (clotting molecules spreading over the polymer)
Inflammation
Apoptosis
Cell death
Hemocomatibility and AKI course
Prolongation of SIRS Hypercatabolism Further glomerular / tubular injury …………
Renal function recovery
Patient outcome
Improving hemo-compatibility Surface treatment (functionalisation):
reduction of electronegativity Coated membranes:
Vit E coating
AN69 membrane
PEI
Cationic group (iminic) Polyethylenimine (PEI),
MW>100 kD
Neutralisation of charged membrane surface
sulfonic group
amine group polyethyleneimine grafted
AN69 ST (surface treated)
DIALYSIS MEMBRANE ELECTRONEGATIVITY, PLASMA KALLIKREIN AND BRADYKININ CONCENTRATION Membrane Zeta potential
(mV) Plasma kallikrein
(U/l) Bradykinin
generation (fmol/min)
AN69 -70+5 60+15 32.100 (26. 500-41.200)
PANDX -60+4 80+20 8.983 (22.600-36.150)
PMMA -25+2 10+5 130 (50-250)
CT -20+2 <5 65 (25-100)
CUP -10+1 <5 78 (25-50)
PS -51+4 <5 62 (25-120)
AN69-ST -15+4 <5 150 (30-450)
Membranes: polyacrylonitrile AN69 (Hospal); PANDX: polyacrylonitrile (Asahi); PMMA: polymethylmetacrylate (Toray); CT, cellulose triacetate (Baxter); CUP: cuprophane (Akzo); PS: polysulfone (Fresenius); AN69-ST, AN69-PEI (Hospal)
- - - - -
- -
- -
- -
- -
- -
- -
Heparin Heparin
+ +
+ +
+ +
+ +
+
PEI PEI
Heparin grafting
o Heparin dose reduction
o No heparin
Heparin grafted membranes
Patients with:
Low platelet count (<90.000/mm3) (NO HIT!)
Recent invasive procedures
Oral anticoagulant therapy
Diabetic retinopathy
Endotoxin (Gram neg bacteria lipolysaccaride) adsorption
Endotoxin Adsorption: 1300 ng/device
Vit E-coated membranes 8 RDT pts; 2 acute HD study sessions: Biocompatible vs VitE coated membranes
Vit E-coated
WHY NOT IN THE AKI PATIENT?
Improving efficiency
High / very high –MW solute
Protein-bound solutes
Superflux dialyzers (high cut off, protein leaking membranes)
Adsorbing membranes
Learning from RDT for the chronic patient
∅ < 0,01 µm ∅ < 0,02 µm
∅ ~ 0,09 µm
∅ ~ 0,30 µm
∅: pore diameter
high flux high cut-off*
protein separation membrane
plasma separation membrane
Electron micrographs of inner membrane surface
Variation of membrane pore size
High Cut-Off membrane
Cut-off ≈ 40.000 Dalton
Increase in: pore size homogeneous pore distribution ↓ Increase in membrane permeability Transfer of protein-bound solutes
Performance of HD membranes and protein permeability
Water permeability
(a) (ml/h/
mmHg/)
Beta2MG clearance (ml/min)
(b)
Albumin loss (grams)
(c)
Sieving Coeff
Beta2MG
Sieving Coeff
Albumin
Low-flux <6 <10 0 --- 0
High flux 20-40 20-40 <0.5 0.7-0.8 <0.001
Protein-leaking
40 >80 2.6 0.9-1.0 0.01-0.03
a) in vitro;
b) includes removal by diffusion, convection, adsorption
c) for 4h conventional HD Ward RA, JASN 2005
Superflux dialyzers on homocysteine levels (270 D, 75% protein-bound)
-20
-15
-10
-5
0
5
10
Superflux
Highflux Lowflux
43 pts, 4 weeks HD, tHcy, % change
De Vriese An S. et al. NDT 2003
*P<0.001
*
Time/weeks
Tota
l hom
ocys
tein
e, µ
mol
/L 45
35 25 15 5
1 12
10 pts, 12 weeks HD, tHcy, abs values
Van Tellingen A. et al. Kidney Int 2001
Superflux
Van Tellingen A et al NDT 2004
25 20 15 10 5 0 -5 -10 -15 -20 -25
Plasma leptin (ng/ml)
Week 1 week 12 week 1 week 12 week 1 week 12 week 1 week 12 F 6HPS TRIC EA 15 G F 60S F 500S
Superflux dialyzers on leptin levels
Superflux F500S
MW 160000 D 12 week observation period
Rhabdomyolysis and renal tubular casts
Glomeruli filtered myoglobin
Water adsorption, myoglobin concentration
Myoglobin, cast foramtion
Myoglobina, MW 16.700 D
Serum myoglobin trend using super high-flux (SHF)
continuos venos-venous hemofiltration (CVVH)
Naka T.
Critical Care 2005
High cutoff dialyzers in rhabdomyolysis
High cutoff hemofiltration in sepsis
Morgera S et al. Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure 34(8), 2006, 2099-2104
→ 30 septic shock patients; CVVH, 48 h, 2.5 lt/h post-dilution → 2:1 high cutoff (n=20; cutoff = 60 kD) or conventional HF (n=10; cutoff = 30 kD)
SAPS score NA changes
Morgera (Berlin), Joannidis (Innsbruck), Risler (Tübingen), Max (Marburg), Schindler (Berlin)
Multicenter study with septeX / HCO in septic AKI
HICOSS (High cut-off sepsis study)
Clark W. 10th Congress of WFSICCM, Florence 2009
Prospective, Randomized, Double-blinded Multicenter study
AKI after SIRS/Septic shock, requiring catecholamines
Primary outcome: 50% reduction of catecholamine requirements by High Cut off-CVVHD Secondary objectives: clinical improvements and safety (albumin levels), SOFA
120 pts
HCO (1.1 m2) Polyamide (1.1 m2)
CVVHD 5 days
CVVHD 5 days
Randomisation
QB 150-200 ml/min
QD 35 ml/Kg/h
QB 150-200 ml/min
QD 35 ml/Kg/h
● Days on Norephrinine (10,0 ±9 vs 11,3 ±9)
● Days on Ventilation (13,9 ±11 vs
16,1 ±11) ● Need for RRT (9,1 ±8 vs 9,5 ±8) ● days in ICU (19±12 vs 19±11)
HCO versus standard high flux
N= 81 pts CVVHD
Membrane A
Membrane B
Membrane A
Membrane BHigh-Flux HCO
Clark W. 10th Congress of WFSICCM, Florence 2009
HICOSS Study results
High cut off dialyzers: not only cytokines
Inflammatory mediators, Beta-2MG, Myoglobulin & light chains: similar MW
κ chain ≅ 22000 daltons λ chain ≅ 44000 daltons
HCO1100 for light chain removal: Malpighi (Bologna) experience
QB 200 ml/min; treatment time 8 hours m
g/dl
1562
8991111
450.6
848 655
570.6353
0
500
1000
1500
2000
Start 4 hours 8 hours Rebound
Lambda Kappa
Kappa: - 68% Lambda: - 58%
RR: Urea: 73.6% - Creatinine 66.3% - Beta-2-microglobuline 42%
Dialysis parameters HD HDF
Qb (ml/min) 200 200
Qd (ml/min) 500 500
Qinf (ml/min) ----- 33
Durata (ore) 8 8
Heparinisation: starting bolus (2000 U), and continuous infusion ACT-driven
Pasquali S et al, Am Soc Nephrology 2008
HCO1100 for light chain removal: diffusion vs diffusion-convection
-70
-60
-50
-40
-30
-20
-10
0
HD HDF
Pasquali S et al, Am Soc Nephrology 2008
HCO1100 for light chain removal: diffusion vs diffusion-convection
Light Chain Removal rate (%)
Adsorbing membranes: a new interest in an old membrane
Blood side
Dialysate side
Ikuo Aoike Nephrol Dial Transplant 2007
a) QUANTITA’ TOTALE DI PROTEINE ASSORBITE
Protein adsorption by PMMA Electrophoresis pa?ern of the
proteins absorbed Radiolabeled beta2-MG and scintigraphic analysis
Protein-bound uremic solutes
Vanholder R, Kidney Int 2003
1000
3000
5000
7000
9000
11000
13000
15000
0 1 2 3 4 PRE POST
• •
6400 6580
10208 12300 12600 14300 12300
Pre (mg/L)
4960 5744 2960 9540 7430
10560 4330
Post (mg/L)
10669.71 +
3092
6503.429 +
2792
-37.2%
P= 0.0071
PMMA – κ chain (HD, 4 hours)
Malpighi Nephrology, (BO), 2011
PMMA – λ chain (HD, 4 hours)
1453.71 +
1306
815.14 +
839
-48.5%
Post (mg/L)
1200 730 743 780 268
2520 3935
540 336 346 308 149
1760 2267
Pre (mg/L)
05001000150020002500300035004000
0 1 2 3 4 PRE POST
• •
Malpighi Nephrology, (BO), 2011
Maximisation of adsorption: resins
Plasma
Reinfusion in
UF out
Mediators adsorbed by the resin
Interleukins
IL1b IL5 IL6 IL7 IL8 IL10 IL16 IL18
Macrophage inflammatory proteins ( MIP1a and MIP1b) Tumor Necrosis Factor a
HYDROPHOBIC RESINS (700 m2/g)
The effect of the kind of the membrane used
Subramanian S et al. Kidney Int 2002
OR CI p
Survival
Synthetic vs cuprophane
1.64 1.10-2.45 0.013
Synthetic vs cellulose acetate
1.20 0.73-1.97 ns
Renal recovery
Synthetic vs cuprophane
1.38 0.80-2.37 ns
Synthetic vs cellulose acetate
1.16 0.72-1.86 ns
Effect of the membranes in the clinical studies
Reduced statistical
power
Different follow-up period
Case-mix
Switch to CRRT
Old membranes
Polysulfone membrane (Fresenius Polysulfon® PS600). Asymmetric, microreticular structure.
Wall thickness 40 µm
Polyethersulfone membrane (DIAPES® HF800). Symmetric, microreticular, three-layer structure.
Wall thickness 35 µm.
Polyethersulfone/polyamid blended membrane (Polyamix®). Asymmetric, anisotrop, macroreticular structure. Wall thickness 50 µm)
The use of the “new” membranes in the clinical practice
Individualized application :
precise aim for the use
different timing for the different membranes (illness phases)
tailored duration of application (illness phases, cost constraints)
Special surveillance to super-flux dialysers:
Albumin loss, but not only albumin loss!
(coagulation factors?, hormones? ….)
Grazie per l’attenzione
Himmelfarb J et al. JASN 2008
Synthetic versus cellulose-based membranes in acute renal failure
Subramanian S et al. Kidney Int 2002
P=0.03
Synthetic membranes (PAN, PMMA, PS): Survival 62%
Cellulose-based membranes: (cuprophane, cellulose acetate): Survival 55%
Renal recovery:
synthetic 53% vs cellulose-based 50%;
Odds Ratio:1.23 (0.90-1.68); p=0.18
Meta-analyses
4 RCT; 3 NRCT; 1 PCS