hd - berliner dialyseseminar

© 2008, Gambro Lundia AB 1

Future development of dialysisWhat is best?

*Berliner Dialyseseminar, 2009

Ingrid Ledebo, Ph.D.Gambro R&D, Lund, Sweden


What is the best dialysis treatment, today and in the future?Survey performed 2007 at:• WCN in Rio de Janeiro• ERA-EDTA in Barcelona• EuRoPD in Helsinki• EDTNA-ERCA in Florence• ASN in San Francisco

Ref: Ledebo, Ronco, NDT Plus, 2009


CAPD/APD

in-center HD/HDF

home and/or self-care HD/HDF

no opinion

What do you consider to be the best initialdialysis treatment for a patient with planned start,today and in the near future?(Assume also chosen by patient, 65 years, one comorbidity)

Q1: Best initial dialysis treatment

Dialysis Opinions 2007


CAPD/APD

in-center HD/HDF (3 times/week)

in-center HD/HDF (>3 times/week)

home and/or self-care HD/HDF (>3 times/week)

no opinion

Q2: Best long-term dialysis treatment

What do you consider to be the best long-termdialysis treatment for the majority of patients,today and in the near future?



low-flux hemodialysis

high-flux hemodialysis

high-volume hemodiafiltration

high-volume hemofiltration

no opinion

Q3: Best extracorporeal form of dialysis

What do you consider to be the best extracorporeal form of dialysis?

synthetic membrane,ultrapure fluid

synthetic membrane,on-line prepared fluid



hard evidence, i.e. improved survival

surrogate evidence, i.e. improved markers (CRP, LVH)

soft evidence, i.e. better quality of lifeown/colleagues´ experience

no opinion

Q4: Minimum level of evidence

In order to consider one form of dialysis superior to another, what is the minimum level of evidence you would require?



What is the best initial dialysis treatment?

Is it…- PD or HD?- in-center or home dialysis?- full-care or self-care dialysis?

CAPD/APD

in-center HD/HDF



Starting with HD or PD, the only RCT1232

773

38HD18

5Tx

9 †

PD20

3Tx

5 †

Ref:Korevaar et al, KI 2003

Conclusion: Non-significant difference in QUALY at start,significantly better survival in PD patients after 5 yrs.

HD

PD


Patient survival in Canada 1991-98 (patients >65, excl. diabetics)

Ref: Fenton and CORR, 2000

PD

HD


Integrative care for dialysis patients

Ref: Van Biesen, JASN, 2000

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 10 20 30 40 50 60 70 80 90 100 110 120

Patients started on PDand transferredafterwards to HDPatients started on HD without transfer

Survival

Months

PD HD

HD

n = 32, 28, 20, 14, 8, 4, for PD to HDn = 224, 135, 82, 42, 27, 19, for HD

p<0.01


Predictors of loss of RRF among incident dialysis patients

Variable Adjusted Odds Ratio

P-value

Female gender 1.45 <0.001

Non-white race 1.57 <0.001

Comorbidity - diabetes 1.82 0.006

- CHF 1.32 0.03

Therapy - PD vs HD 0.35 0.001

- ACE-inhibitor 0.68 <0.001

- Ca channel-blocker 0.77 0.01

Ref: Moist et al, JASN, 2000

National random sample of 1843 incident dialysis patients (1032 on PD) with control for baseline variables. Loss of RRF= urine volume< 200 ml/24 h after 1 yr.


Impact of dialysis mode before Tx

Ref: Goldfarb-Rumyantzev et al, AJKD 2005

RRT mode before Txin relation to HD

Graft survivalHR p

Recipient survivalHR p

PD immediately before Tx 0.97 <0.05 0.94 <0.001

PD predominantly (>50%) 0.97 <0.05 0.96 <0.05

PD only 0.93 <0.002 0.9 <0.001

PD + Tx 0.87 <0.05 0.98 ns

PD + HD 1.09 <0.001 1.1 <0.001

Cox model used for all USRDS data 1990-1999, n=92 844

Conclusion: PD before Tx has a protective effect on graft and recipient survival

© 2008, Gambro 13

Patient choice of initial dialysis modality in NECOSAD

Ref: Jager et al, AJKD 2004

incident patientsn = 1347

personal choicen = 864

some contra-indications

n = 483

PD n = 416

HDn = 448

HDcontraind to PD

n = 386

PD contraind to HD

n = 97

64% 36%

48% 52% 80% 20%

© 2008, Gambro 14

Impact of predialysis eduction on modality choicein Brussels

incident patients n = 242

pre-dialysis

educationn = 185

in-center HDfor medical

reasonn = 57

preemptivetrans-

plantationn = 8

PDn = 55

HDself-care in satellite

n = 30

HDself-careat home

n = 17

in-center HD

n = 75

76% 24%

self-care dialysis, n = 102 (55%)

Ref: Goovaerts et al, NDT 2005

4% 40%


How are the incident patients treated? USRDS data by first modality

Ref: USRDS 2009 ADR

Total dialysis

HD

PDTx


Best initial dialysis treatmentaccording to 6 595 nephrology professionals

0

10

20

30

40

50

60

CAPD/APD

in-centerHD/HDF

home a/o self-care HD/HDF

no opinion



Best initial dialysis treatmentworldwide opinion by nephrology professionals

0

10

20

30

40

50

60

Total (6595)

W Europe(2071)

E Europe(1879)

Asia (888)

Americas(1107)

CAPD/APD in-center HD/HDF home/sc HD/HDF



Best initial dialysis treatmentin the world, in W Europe and in Germany in 2007

0

10

20

30

40

50

60

Total (6595) W Europe (2071) Germanic (266)

CAPD/APD in-center HD/HDF home/sc HD/HDF

19

49.5%

22.4%

24.9%

3.2%

CAPD/APD

in-center HD/HDF


no opinion

What do you consider to be the best initialdialysis treatment for a patient with planned start,today and in the near future?(Assume also chosen by patient, 65 years, one comorbidity)

Q1: Best initial dialysis treatment


What is the best long-term dialysis treatment?

Is it …- PD or HD/HDF?- in-center or home dialysis?- full-care or self-care dialysis?- conventional or more frequent dialysis?

CAPD/APD





Adjusted five-year survival, by modality & primary diagnosis

Surv

ival

pro

babi

lity

Ref: USRDS 2009 ADR

© 2008, Gambro 22

Survival on Home HD vs in-center HD

0 0,5 1 1,5

adjustment2

adjustment1

unadj.

home HD in-center HD

adj for age, race, sex and PRD

additionally adj for comorbid conditions

n = 3102n = 70

Relative mortality risk with 95% CI

Ref: Woods et al, KI,1996

© 2008, Gambro 23

Survival on Daily Dialysis vs 3x/week

0 0,5 1 1,5

Ref: Blagg et al, HDI, 2006

0 10 20 30

Expected deaths SMR

p<0.005DD DD

HD HD

HD =dialysis 3 times/w DD = dialysis ≥5 times/week

117 patients on Short Daily Dialysis >1 year in Seattle, 84% at home. SMR calculated acc to USRDS, adjusted for age, sex, race and PRD.

Conclusion: 61% better survival of patients on Daily Dialysiscompared to HD patient of same age and background


Ref: Kjellstrand et al, NDT 2008

415 patients treated with Short Daily Dialysis

20 – 44 yrs 45 – 64 yrs

USRDSUSRDS

Daily Dialysis

Daily Dialysis

Survival on Daily Dialysis vs USRDS data


Survival on Daily Dialysis at home vs in-center

Daily at home

Daily in-center

USRDS all HD

Ref: Kjellstrand et al, NDT 2008

© 2008, Gambro 26

Survival on frequent nocturnal dialysis

Ref: Pauly et al, NDT 2009

NHD

DTXLTX

Canadian NHD patients amd matched USRDS transplant patients

© 2008, Gambro 27

Frequent dialysis – effect on the heartAuthor Study

typeN LVH (g/m2)

frequent vs conv. dialysis

Time(months)

p

Pierratos 2001

obs 21 162 =>117

no change

154 => 108

145 => 155

92.4 => 85.3

101.8 => 102.8

25 0.02

Ayus2005

cohort 26+51

12 0.001

Culleton2007

RCT 26 +25

6 <0.05

© 2008, Gambro 28

How are the prevalent dialysis patients treated around the world?

Ref: USRDS 2009 ADR


Best long-term dialysis treatmentaccording to 6 595 nephrology professionals

0

10

20

30

40


CAPD/APD in-center HD/HDF

home/self-care HD/HDF

no opinion

3x/w >3x/w >3x/w


Best long-term dialysis treatmentworldwide opinion by nephrology professionals

0

10

20

30

40

50

Total (6595)

W Europe(2071)

E Europe(1879)

Asia (888)

Americas(1107)

CAPD/APD in-center HD/HDF, 3x/win-center HD/HDF, >3x/w home/sc HD/HDF, >3x/w



Best long-term dialysis treatment?opinion vs reality

0

10

20

30

40

50

60

70

80

90

100

CAPD/APD

in-center HD/HDF

3x/w >3x/w


0

10

20

30

40

50

60

70

80

90

100

in-centerHD/HDF

3x/w

>3x/w

6 595 opinions 1.5 million patients

>3x/w

CAPD/APD


Ref: Ledebo, Ronco, NDT Plus 2008


Which dialysis option would you preferif you needed dialysis and could not be transplanted? Question to 70 Scottish nephrologists 2009

0

20

40

60

80

100

% o

f res

pond

ents

Where? Mode? How?

at home(94%)

HD(84%)

PD

HD

HDF

daily and/orlong duration

Ref: McManus et al, ASN abstract, 2009


Best long-term dialysis treatmentin the world, in W Europe and in Germany, 2007

0

10

20

30

40


CAPD/APD in-center HD/HDF, 3x/win-center HD/HDF, >3x/w home/sc HD/HDF, >3x/w

34

8.0%

9.1%

23.6%

58.0%

1.3%

CAPD/APD




no opinion

What do you consider to be the best long-term dialysis treatment for the majority of patients,today and in the near future?

Q2: Best long-term dialysis treatment






What is the best extracorporeal form of dialysis ?

Is it to use…- low-flux or high-flux membrane? - diffusion or convection?- how much convection?

© 2008, Gambro 36

Membrane permeability

© 2008, Gambro 37

Uremic toxins

Established:

Suspected:

© 2008, Gambro 38

EuTox: Known uremic retention solutes

Ref: Vanholder el al. KI Suppl, 2003

Small, water-soluble Protein-bound Middle molecules

© 2008, Gambro 39

Convection in dialysis therapies

chronic dialysis therapy

membrane UF volume convection

low-flux dialysis (HD)

low-flux weight loss very little

high-flux dialysis (HD)

high-flux weight loss + backfiltration

little, uncontrollable

hemodiafiltration (HDF)

high-flux weight loss + substitution

considerable, controllable

hemofiltration (HF)

high-flux weight loss + substitution

considerable, controllable

© 2008, Gambro 40

HD HFHDF

Clearance profiles in HD, HDF & HF

Conditions: QB=300 ml/min, QD=800 ml/min, same membrane, weight loss= 10 ml/min; postdilution HDF w UF=120 ml/min; predilution HF w UF= 450 ml/min

Ref: Leypoldt, NDT, 2000


Outcome with high-flux dialysisLarge RCT, all patients• HEMO Study, RCT• MPO Study, RCT

Large RCT, secondary & subgroup analysis• HEMO Study, RCT• MPO Study, RCT

Large prospective studies• French nutrition study• 4D, German RCT, statin & diabetics, post-hoc analysis


Outcome with high-flux dialysis

Large RCT, all patients• HEMO Study, RCT • MPO Study, RCT

Ref: Locatelli et al, JASN 2009Ref: Eknoyan et al, NEJM, 2002


Outcome with high-flux dialysisLarge RCT, secondary & subgroup analysis• HEMO Study, RCT • MPO Study, RCT

factors subgroups dose effectp - value

flux effectp - value

age ≤ 58 yrs >58 0.92 0.69

gender male female 0.014 0.27

race black non-black 0.06 0.24

diabetes + - 0.35 0.87

dialysis yrs ≤ 3.7 yrs >3.7 0.12 0.005

albumin ≤ 3.6 g/dl >3.6 0.16 0.65

comorbidity ≤ 2 units >2 0.96 0.96

long-term dialysis patients

Ref: Locatelli et al , JASN 2009

high-flux

low-flux

p=0.032

dialysis patients with alb < 4.0 g/dL

high-flux

p=0-039

low flux

diabetic patients

Ref: Eknoyan et al, NEJM, 2002

Survival benefit with high-flux HD, version 1.2 © 2008, Gambro Lundia AB 44

Ref: Cheung et al, JASN 2003

Ref: Delmez et al, AJKD 2006

High-flux dialysis – certain mortality causes


Outcome with high-flux dialysisLarge prospective studies• French nutrition study • 4D, German RCT

Ref: Krane et al, AJKD 2007

high-fluxsynthetic

low-fluxsynthetic

Ref: Chauveau et al, AJKD 2005

high-flux

low-flux


High-flux dialysis and outcome

0 0,2 0,4 0,6 0,8 1

Krane 06

Chauveau 05

Delmez 06

Cheung 05

Locatelli 09

Locatelli 09

Cheung 03

Locatelli 09

Eknoyan 02

ReferenceLow-flux

HEMO

MPO

HEMO

MPO

MPO

HEMO

HEMO

French

4D

p-values

n.s.

n.s

0.001

0.01

0.056

0.042

0.016

0.01

0.0006

>3.7 yrs

alb<4.0

diab.

cardiac †CBV †

all

all

© 2008, Gambro 47

<20 20 - 27.5 Cumulative mean predialysis serum ß2m (mg/L)

Rel

ativ

e R

isk

personal extrapolation

Serum β2m levels and mortality in the HEMO study

Based on: Cheung et al, JASN 2006


Pre-dialysis β2m and treatment mode

Conclusion: The more convection the lower plasma level of β2m

© 2006 Gambro


Outcome with HDF/HFLarge observational trials• on-line HDF vs hf HD in Euclid database• on-line HDF vs HD in DOPPS European database• on-line HDF vs hf HD in UK center• double-hf HDF vs all other in US center

RCT• on-line, predilution HF vs lf HD• on-line HDF vs lf HD, CONTRASTstudy ongoing


HDF is associated with 37% lower mortality in the EUCLID database

variable reference odds ratio 95% cilower

95% ciupper

p-value

age per year 1.054 1.045 1.063 <0.001

gender female 1.207 0.990 1.470 0.063

diabetes absent 1.664 1.323 2.094 <0.001

neoplasm absent 1.387 1.037 1.856 0.027

time on RRT

per year 1.041 1.021 1.062 <0.001

on-line HDF

HD 0.626 * 0.426 0.921 0.017

Ref: Jirka et al, NDT 2005, Suppl 5

* adjusted for age, gender, co-morbidities and time on RRT444 patients on on-line HDF compared to 3331 patients on hfHD


Mortality risk HDF vs HD

0

0,2

0,4

0,6

0,8

1

1,2

1,4

low-flux HD high-flux HD low-effic HDF high-effic HDF

Rel

ativ

e ris

k of

mor

talit

y

reference p=0.83 p=0.68 p=0.01

1.030.93

0.65

(1366) (546) (156) (97)

Ref: Canaud et al, KI 2006Ref: Canaud et al, KI 2006

n = 2165, adjusted for age, sex, time on dialysis, comorbidity, weight, catheter, Hb, alb, nPCR, lipids, Kt/V, EPO, QoL


Ref: Vilars et al, CJASN, 2009

Cox prop hazards model• HR = 0.454 p= 0.000 for patients predominantly treated with HDF• HR = 1.030 p=0.000per year of increasing age• HR = 1.848 p= 0.000 for malignancy• HR = 1.339 p= 0.006for diabetes

152 000 session of on-line HDF in 232 patients compared to 291 000 sessions on hfHD in 626 patients


Convective therapies and outcome

0 0,2 0,4 0,6 0,8 1 1,2

Santoro, 2008

Bosch, 2006

Vilar, 2009

Canaud, 2006

Jirka, 2005

Reference, HD p n

0.017 3828

0.01 4504

0.001 858

<0.005 183

<0.05 64

Relative risk of death

HDF

HDF

HDF

HF, RCT

HDF


CONTRASTThe Dutch Convective Transport StudyProspective, randomized, multicenter trialApprox. 780 patients randomized to on-line HDF & low-flux HD followed for up to 3 yearsPrincipal Investigators:Dr PJ Blankestijn, Utrecht MCProf Dr PM ter Wee, Free University MC, Amsterdam

© 2008, Gambro 56

Evidence for outcome benefits with high-flux/convective therapies

• long-term dialysis patients• hypoalbuminemic patients• diabetic patients• reduced cardiac death• reduced cerebrovascular death


Best extracorporeal form of dialysisaccording to 6 595 nephrology professionals

0

10

20

30

40

50


low-flux HD

high-flux HD

high-volume HDF

high-volume HF


Best extracorporeal form of dialysisworldwide opinion by nephrology professionals

0

10

20

30

40

50

60

Total (6595)

W Europe(2071)

E Europe(1879)

Asia (888)

Americas(1107)

low-flux HD high-flux HD high-volume HDF high-volume HF



Best extracorporeal form of dialysisin the world, in W Europe and in Germany in 2007

0

10

20

30

40

50

60


low-flux HD high-flux HD high-volume HDF high-volume HF

60

3.3%

25.3%

63.6%

1.9%

5.9%





no opinion

What do you consider to be the best extracorporeal form of dialysis?

Q3: Best extracorporeal form of dialysis

synthetic membrane,ultrapure fluid

Syntheticmembrane,on-line prepared fluid




soft evidence, i.e. better quality of lifeown/colleagues´ experience

Which level of evidence do we require?


Lowest number of RCT in nephrology

Ref: Strippoli, JASN 2004


Minimum level of evidenceaccording to 6 595 nephrology professionals

0

10

20

30

40

50

hard evidence surrogate evidence soft evidence experience



Minimum level of evidenceworldwide opinion by nephrology professionals

0

10

20

30

40

50

60

Total (6595)

W Europe(2071)

E Europe(1879)

Asia (888)

Americas(1107)




Minimum level of evidencein the world, in W Europe and in Germany in 2007

0

10

20

30

40

50



66

48.7%

17.0%

28.0%

3.7%

2.6%



soft evidence, i.e. better quality of life

own/colleagues´ experience

no opinion

In order to consider one form of dialysis superior to another, what is the minimum level of evidence you would require?

Q4: Minimum level of evidence


Future development of dialysis Conclusions from survey 2007

• The opinion of nephrology professionals on the value of therapies follows scientific discussions in spite of lack of hard evidence• PD considered best therapy for incident patients• Self-care dialysis at home, frequently applied, considered best long-term therapy• High-flux membranes strongly preferred to low-flux membranes • When possible use high-flux membranes for maximum convective transport, i.e. in HDF• Opinions differ greatly from present situation and can be seen as indication of future development of dialysis


multiple drug therapy that stops progressionstem cell therapy that restores renal functionprepare for dialysis with miniaturized, wearable, bionic kidney that works continuouslyprepare for dialysis similar to what we have todayother/no opinion

Q5: Best ESRD treatment in 2025Which ESRD treatment do you think you will be able to recommend to a close family member in 2025, when he/she turns 60 and is found to have CKD stage 4?


69

19.5%

31.5%

28.9%

16.0%

4.2%

Which ESRD treatment do you think you will beable to recommend to a close family member in 2025,when he/she turns 60 and is found to have CKD stage 4?

Q5: Best ESRD treatment in 2025

multiple drug therapy that stops progression

stem cell therapy that restores renal function

prepare for dialysis with miniaturized, wearable, bionic kidney that works continuously

prepare for dialysis similar to what we have today

other/no opinion


Best ESRD treatment in 2025according to 6 595 nephrology professionals

0

10

20

30

40

50

preventive drugs stem cells bionic WAK dialysis no opinion



Best ESRD treatment in 2025worldwide opinion by nephrology professionals

0

10

20

30

40

50

Total (6595)

W Europe(2071)

E Europe(1879)

Asia (888)

Americas(1107)

preventive drugs stem cells bionic WAK dialysis



Best ESRD treatment in 2025in the world, in W Europe and in Germany in 2007

0

10

20

30

40

50


preventive drugs stem cells bionic WAK dialysis

hd - berliner dialyseseminar

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