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