1. How Technological Developments make better Treatment a Reality
From complex dream to simple reality: HighVolumeHDF – the standard therapy of the future. NOW!
How Technological Developments make better Treatment a Reality
Angelika Kneppel
Fresenius Medical Care, Germany
EDTNA Corporate Education Session
Malmö, Sept. 1st, 2013

2. Randomized controlled clinical trial with positive primary outcome!
The new Catalonian HighVolumeHDF study shows: HighVolumeHDF improves patient survival
Improved survival
30%
risk reduction in all-cause mortality (p=0.01)
33%
risk reduction in cardiovascular mortality (p=0.06)
55%
risk reduction in mortality from infection (p=0.03)
61%
risk reduction in mortality from stroke (p=0.03)
Better patient well-being
28%
risk reduction in incidence of hypotensive episodes (p<0.001)
In recent years several studies have already confirmed the benefits of haemodiafiltration (HDF).
The latest, the Catalonian HighVolumeHDF study of the ESHOL study group, proves the benefits of this therapy beyond doubt.
The randomized controlled clinical trial shows a significant risk reduction of all-cause mortality, a significantly reduced risk of incidences of hypotensive episodes as well as significantly less hospitalisation days – just to name some of the major findings.
This means our long-lasting conviction in HDF is now widely shared across the scientific community and finally backed by evidence.
1,2,3,4
Randomized controlled clinical trial with positive primary outcome!
Reduced treatment costs
22%
risk reduction in all-cause hospitalisation (p=0.001)
Maduell F et al, J Am Soc Nephrol. 24 (2013)
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

3. From ONLINE HDF to HighVolumeHDF
ONLINE stands for the preparation of the substitution fluid directly by the dialysis machine.
To achieve large substitution volumes therapeutic aspects have to be considered.
This therapy approach is what we call HighVolumeHDF.
Why are we now talking about HighVolumeHDF and no longer about ONLINE HDF?
The ONLINE preparation of the substitution fluid for performing haemodiafiltration therapy was the major milestone in the evolution of this therapy. The cumbersome connection of several fluid bags became obsolete once the technology of the dialysis machines enabled the safe preparation of the infusion fluid. Nowadays, the ONLINE preparations is available at all HDF capable dialysis machines. Although there are still differences in terms of handling or cost the availability of sufficient substitution fluid is no more a limiting factor for the therapy prescription.
With the latest knowledge of the recent studies large amounts of substitution fluid (>21L/treatment) should be delivered per treatment. To achieve this target volume therapeutic aspects have to be considered. This therapy approach is what we at Fresenius Medical Care call HighVolumeHDF.
ONLINE was a technology for water preparation, HighVolumeHDF is THE therapy approach.
ONLINE was a technology for water preparation, HighVolumeHDF is THE therapy approach.
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

4. Automated integrity test
Water quality for HighVolumeHDF requires the same international standards as for High-Flux HD*
The combination of Online Purification Cascade & ONLINEplus at 5008 CorDiax / 5008S CorDiax
fulfils the required international standards1,2
ONLINEplus – Double-stage filtration system
Automated integrity test
Unlimited
sterile, non-pyrogenic substitution fluid
Reverse Osmosis (RO)
Ready-made concentrate fluid
Talking about automatically prepared sterile, non-pyrogenic substitution fluid the question about special requirements for the water preparation system is frequently raised.
The answer to this question is straightforward: The international standards require the same water quality no matter if you want to perform high-flux dialysis or haemodiafiltration. Please take note that local regulations may have additional requirements.
Dialysis fluid
1 ISO 13959: ISO 23500:2011
* Local regulations may differ
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

5. The Catalonian HighVolumeHDF study is part of a bigger picture…
30% Risk reduction in all-cause mortality vs. high-flux HD (p=0.01)
(*High efficiency = Sub. volume > 21L)
DOPPS (2005):
High-efficiency* HDF reduces mortality risk (35 %) compared to Low-Flux HD (p=0.01)
(*High efficiency = Sub. volume 15–24.9 L/session)
All have one in common – Volume matters!
Contrast (2012):
High-volume HDF* considerably reduces mortality risk compared to low-flux HD (p=0.003)
(*High-volume ≥21.95 L)
Turkish (2011):
HDF treatment with substitution volume › 17.4 L provides better cardiovascular and overall survival compared to high-flux HD (p=0.03)
The Catalonian HighVolumeHDF study is part of a bigger picture. Starting with DOPPS in 2005, the CONTRAST and the TURKISH study have also shown that patients being treated with higher substitution volumes achieved better outcomes. So there is a clear trend to be seen – volume matters!
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

6. Volume matters – but how much is high-volume?
But how much is high-volume? How can we define high substitution volume?
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

7. Volume matters – but how much is high-volume?
Total convective volume
per treatment1
~ 23 L
1 Delivered median volumes based on Maduell F. et al. 2013
Objective of HighVolumeHDF:
Vsub ≥ 21 L in postdilution
target substitution volume per treatment (without weight loss) for all patients
No negative impact with (too) high substitution volume is known yet
Achieving high substitution volumes requires good blood flow but also technology designed for HighVolumeHDF
Substitution volume
21 L
Weight loss
~ 2 L
First of all it is important to understand the different definitions:
The total convective volume or total ultrafiltration volume is made up of the weight loss, in this example 2L, and the substitution volume, which should reached at least 21L - resulting in 23L convective volume for this treatment. The threshold value of 21L is taken from the latest Catalonian study.
Is there a potential negative effect of too high-volumes? A negative impact of high substitution volumes has not been seen yet. Achieving high substitution volumes without leading to high transmembrane pressure (TMP) requires good blood flow but also technology designed for HighVolumeHDF
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

8. Achieving high substitution volume - blood flow limits the performance
Performance limits in post-dilution HDF (schematic diagram)
Rule of thumb
– Filtration Fraction [FF]
blood inlet
blood outlet
QUF
~ 25% QB
Filterable
plasma water
Qspost
Protein/ Protein bound water
Example:
QB = 320 mL/min
FF = 25 %
 Qcon = 80 mL/min
QUF = 10 ml/min
 Qspost = 70 mL/min
 Vsub = 17 L
Haematocrit
Why is a high blood flow important for achieving high substitution volumes?
Only a small share of the blood flow rate is accessible for ultrafiltration. As a rule of thumb 25% of blood flow can be removed. This is also called filtration fraction.
Let‘s have a look at the following example:
The blood flow is 320 mL/min, with a filtration fraction of 25% a convective flow of 80 mL/min is possible. To calculate the substitution volume we have to subtract the ultrafiltration rate, let‘s assume 10 mL/min (corresponding to 2.4L). This means the substitution pump can be set to a value of 70 mL/min and consequently after 4hrs treatment nearly 17L substitution volume will be achieved.
So the higher the blood flow the higher the substiution volume will be. QB
QB = Blood flow rate ; Qcon = convective flow rate
Qspost = Substitution flow rate in post-dilution mode; QUF = Ultrafiltration rate (weight loss);
FF = Filtration Fraction; Vsub = Substitution volume;
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

9. Crucial factors for HighVolumeHDF therapy - it is not just a matter of blood flow …
5008S CorDiax & 5008 CorDiax
AutoSub plus
MIXED HDF
Patient related:
Therapy driven:
High effective blood flow +
Convective dose
(= max. substitution) + + +
FX CorDiax HDF
Good rheological conditions +
Optimal filtration flow +
However, it is not just a matter of blood flow. There are other factors which can also have an impact on the achievable substitution volume.
Patient related factors are blood flow, which could possibly be improved by using larger needles, and the rheological conditions, e.g. viscosity of the blood.
Therapy or prescription related factors are the convective dose, which is deliveder by the dialysis machine and the optimal filtration flow, which requires suitable membranes and dialysers.
Not to forget treatment time, which naturally has an impact on the treatment quality.
Treatment time
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

10. Achieving high volumes is also a matter of using technology designed for HighVolumeHDF
How to set-up the substitution volume?
PAST
TODAY
How is the convective dose set?
There are differences depending on the machine technology.
4008 H
ONLINEplus®
“Advanced online
Preparation with
DIASAFE®plus”
5008
Therapy System
“Online haemodiafiltration
as standard treatment”
5008 CorDiax &
5008S CorDiax
“With AutoSub plus HighVolumeHDF
becomes as simple and safe as HD”
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

11. Starting point: Haemodiafiltration with manual volume control
Requires manual calculation, setting & adaptation of the substitution rate during the treatment
Example:
QB = 320 mL/min
Qcon = 80 mL/min
QUF = 10 ml/min
Qspost = 70 mL/min
In manual mode the user has to calculate at treatment start the substitution rate, enter it as prescription and reduce the rate during the treatment if it becomes necessary due a increase in transmembrane pressure or hemoconcentration risk.
It is the responsibility of the nurses to control the pressure and reduce the sub rate if necessary. So, the sub rate is normally set to a more conservative value to avoid pressure increases. Consequently the sub volume tends to be lower.
Manual setting of substitution rate
 Sub volumes tend to be lower than possible
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

12. Milestone 1: AutoSub in 5008 Therapy System
Objective: Automatic setting of substitution rate for alarm-free treatment
Substitution rate automatically calculated via formula (based on Hct, TP, dialyser type, UF and TMP drift)
Automatic decrease of substitution rate in case of pressure increase
A formula never considers all parameters with impact on flow conditions & blood viscosity
User has to enter patient’s latest available lab values
Calculation and automatic decrease of substitution rate
The development of a system which can automaticatally set the sub rate for an alarm-free treatment was the first milestone at the 5008 Therapy System
The substitution rate is now automatically calculated via a specific formula (based on Hct, TP, dialyser type, UF and TMP drift)
The rate is set by the machine and automatically decreased in case of a pressure increase.
Although this system is already much better than a manual setting and adaption there are some drawbacks:
a formula never considers all parameters with impact on flow conditions & blood viscosity
User has to enter patient’s latest available lab values
 Sub volumes still tend to be lower the patient individual maximum .
 Sub volumes tend to be lower than possible
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

13. Milestone 2: AutoSub plus in 5008 CorDiax*
Objective: Automatic maximisation of substitution rate for alarm-free treatment
5008 CorDiax
5008S CorDiax
The objective of the continuous development of the 5008 machines was no longer only the automatic setting but the automatic maximisation of the substitution rate.
* and 5008S CorDiax
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

14. The challenge of HighVolumeHDF: Maximizing substitution volume in daily clinical practice
Haemo-concentration
Convective volume
However, to achieve high substitution volumes in daily clinical practice a constant balance between the total ultrafiltration (substitution volume plus weight loss) and the potential hemoconcentration in post-dilution HDF has to be maintained. This is leading either to low substitution volumes (to avoid the problem) or to frequent pressure alarms during treatment with the risk of filter clotting.
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

15. Changing the perspective is the key for more performance
Today
Dynamic Signal analysis of pressure pulses
-> along the blood flow pathway
New +
Static Transmembran Pressure P P
TMP
To maintain the optimal balance a change of the perspective is the key for more performance.
Currently, the TMP is the parameter which is driving the decision to adapt the substitution rate. This is what we consider as outside information.
With our new feature we change the perspective as we get also in „inside“ information. The Dynamic Signal analysis of pressure pulses provides detailed information of pressure changes along the blood flow pathway. P P
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

16. Functional principle of AutoSub plus4
Optimal Performance
= highest substitution rate at any time
Leading to 3 1
Autoregulation Immediate adaptation (up or down) of substitution rate to the current treatment conditions
Changing conditions along the blood flow pathway of the dialyzer (e.g. flow conditions due to haemoconcentration) P
TMP + 2
Dynamic Signal Analysis of Pressure Pulses Permanent measuring & evaluating of conditions along the blood flow pathway in the dialyzer
AutoSub plus is constantly analysing the conditions along the blood flow pathway of the dialyser. In case there is a change the autoregulation will immediately adapt the substitution rate to the current treatment conditions. This goes in both directions decrease as well as increase of substitution rate. This is leading to an optimal performance at any time during treatment.
Triggers
Detected by
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

17. Milestone 2: AutoSub plus in 5008 CorDiax*
Objective: Automatic maximisation of substitution rate for alarm-free treatment
Very precise information on the conditions in the dialyser is available
- not just across the membrane but also along the blood flow pathway.
Several checks per minute
enable the continuous optimization of the substitution rates (decrease & increase).
The system is automatically activated at start of treatment
5008 CorDiax
5008S CorDiax
Dynamic analysis of pressure pulses along the blood flow
pathway!
Why are we now better in maximizing substitution volumes with AutoSub plus?
Very precise information on the conditions in the dialyser is available
- not just across the membrane but also along the blood flow pathway.
Several checks per minute
enable the continuous optimization of the substitution rates (decrease & increase).
The system is automatically activated at start of treatment.
Not even pressing a button is required once HDF is prescribed the automatic regulation will run
 This is resulting in individually maximised sub volumes and in higher filtration fraction .
Measurement + automatic adaptation (up or down)
 Sub volume is individually maximised resulting in higher filtration fraction
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

18. Each Increase in Filtration Fraction pays off
When we remember the rule of thumb the filtration fraction was 25%. With AutoSub plus higher filtration fractions can be seen for many treatments.
Each Increase in Filtration Fraction pays off:
When the filtration fraction is increased from 25% to 30%, the target sub volumen of 21L can already be achieved with a blood flow of 320mL/min instead of 385 mL/min.
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

19. Dynamic analysis of pressure pulses along the blood flow
Achieving high volumes is also a matter of using technology designed for HighVolumeHDF
PAST
TODAY
New
Manual
volume control
AutoSub
AutoSub plus
4008
The last diagram clearly shows achieving high volumes is not just a matter of blood flow but also a matter of using technology designed for HighVolumeHDF. As this technology can help to increase the filtration fraction.
Dynamic analysis of pressure pulses along the blood flow
pathway!
Setting of sub rate
Calculation + automatic decrease of sub rate
Measurement + automatic adaptation (up or down) of sub rate
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

20. Suitable dialyser for HighVolumeHDF
The new Helixone®plus membrane of the FX CorDiax series
improves the removal of middle molecules while ensuring the retention of albumin
Increased inner fibre lumen of the FX CorDiax HDF dialysers
facilitates optimal flow conditions for maximal performance
FX CorDiax 600
FX 600
Next to the right machine technology the dialyser should also support HighVolumeHDF . As during haemodiafiltration the convective transport should be increase the membrane should have high sieving coefficients for middle molecules like ß-2 microglobuline and myoglobuline. The FX CorDiax dialysers with the currently highest sieving coefficients improve the removal of middle molecules while ensuring the retention of albumin.
Furthermore, the inner fibre lumen has a major influence on the flow rate. The smaller the diameter the higher the pressure. Therefore a large inner diameter, i.e. 210 µm of the FX CorDiax HDF dialyser, facilitates optimal flow conditions.
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

21. Achieving adequate substitution volumes
Achieving adequate substitution volumes* is facilitated by using the right technology
AutoSub plus
Automatic maximisation of substitution volume in HighVolumeHDF
FX CorDiax HDF dialysers
facilitate optimal flow conditions for maximal performance
improve the removal of middle molecules while ensuring the retention of albumin
In combination with FX CorDiax HDF dialysers, AutoSub plus maximizes substitution volumes in post-dilution HDF in a highly safe manner compared to conventional methods.
To summarize the features: Achieving adequate substitution volumes* is facilitated by using the right technology
AutoSub plus
Automatic maximisation of substitution volume in HighVolumeHDF
FX CorDiax HDF dialysers
facilitate optimal flow conditions for maximal performance
improve the removal of middle molecules while ensuring the retention of albumin
In combination with FX CorDiax HDF dialysers, AutoSub plus maximizes substitution volumes in post-dilution HDF in a highly safe manner compared to conventional methods.
* (>21 L / session)
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

22. The right technology for HighVolumeHDF - Benefits of AutoSub plus
The fully automatic regulation means no additional work for the nurses: neither in setting the right pump speed nor in assuring trouble-free treatment.
In daily routine this comes down to a safe and simple application of HighVolumeHDF for a large number of patients.
AutoSub plus supports the nephrologist to prescribe high substitution volumes even with „average“ blood flows.
More patients will be able to reach high substitution volumes and benefit from the positive outcomes of HighVolumeHDF.
The right technology for HighVolumeHDF - Benefits of AutoSub plus:
The fully automatic regulation means no additional work for the nurses: neither in setting the right pump speed nor in assuring trouble-free treatment.
In daily routine this comes down to a safe and simple application of HighVolumeHDF for a large number of patients.
AutoSub plus supports the nephrologist to prescribe high substitution volumes even with „average“ blood flows.
Finally, more patients will be able to reach high substitution volumes and benefit from the positive outcomes of HighVolumeHDF.
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013

23. Thank you
EDTNA CES HighVolumeHDF - © Copyright Fresenius Medical Care Sept 2013