HDxTHERAPY

Enabled by

Making possible personal.

COMPLEMENT FACTOR D

PHOSPHATE

INTERLEUKIN-6

LAMBDA FREE LIGHT CHAINS

UREA

BETA 2 MICROGLOBULIN

CREATININE

* Do not use THERANOVA dialyzers in HDF or HF mode

THE NEXT HORIZON IN DIALYSISIS CLOSER THAN YOU THINKHDx BY THERANOVA EXPANDS YOUR RENAL POSSIBILITIES

The new HDx therapy (expanded HD) is the next evolution in hemodialysis, as it effectively targets the removal of large middle molecules.1 Indeed, many of them are linked to the development of inflammation, cardiovascular disease, and other co-morbidities in dialysis patients.2

Not only can HDx therapy provide HDF performance and beyond in the removal of conventional middle and large middle molecules, it does so using regular HD workflow and infrastructure.3

The HDx therapy is enabled by the THERANOVA* dialyzer featuring an innovative membrane that combines a higher permeability than regular high-flux dialyzers with effective selectivity for large proteins.4,5

This new therapy opens up a new option for dialysis patients who are believed to benefit from effective removal of large uremic toxins, for clinics that want expanded dialysis performance without the added burden of HDF.

PHOSPHATE(96 Da)

CREATININE(113 Da)

LAMBDA FREE-LIGHT-CHAINS

(45,000 Da)

HDx

CYSTATIN C(13,300 Da)

HDF

HD

UREA(60 Da)

PTH (9,500 Da)

BETA 2 MICROGLOBULIN

(11,800 Da)

COMPLEMENT FACTOR D(24,000 Da)

ALPHA-1 MICROGLOBULIN

(33,000 Da)

CHANGE ONE THINGCHANGE EVERYTHINGEXPLORE THE HDx THERAPY BY THERANOVA

Mortality from cardiovascular and infectious events in HD remains unsatisfactorily high with current dialytic therapies.6 Large middle molecules have been associated with inflammation, cardiovascular events and other dialysis-related comorbidities.2 Current dialytic therapies, though efficient in removing small solutes, have limited capability in removing large middle molecules.7

HDx is a new therapy targetting an efficient removal of large middle molecules, without the need for a more complex setup than in regular HD. The HDx therapy is delivered with an innovative dialyzer featuring a new type of membrane, combining a higher permeability than high-flux dialyzers with effective selectivity to retain essential proteins.4,5

CATEGORIZATION OF UREMIC SOLUTES Non-protein bound uremic solutes accumulating in chronic kidney disease can be divided into three main categories.5

Small molecules < 500 DaEffective removal by diffusion

Conventional middle molecules 500 - 15,000 DaLimited removal by diffusion, compensated by applying convection

Large middle molecules 15,000 - 60,000 DaRequire higher permeability membranes for effective removal

HDx enabled by

CO-MORBIDITIES

ENDOTHELIAL DYSFUNCTION

PROTEIN-ENERGY WASTING PROGRESSION OF CARDIOVASCULAR DISEASES

VASCULAR CALCIFICATION

OXIDATIVE STRESSINFLAMMATION

RETENTION OF UREMIC SOLUTES

REDUCED APPETITE INCREASED CATABOLISM

INFECTIOUS COMPLICATIONS

SHIFTING FOCUS TOLARGE MIDDLE MOLECULESEXAMINING UREMIC TOXINS BEYOND BETA 2 MICROGLOBULIN

There is growing evidence showing a link between large middle molecules and the development of different outcome-related morbidities:

Complement factor D (24 kDa)

α1-microglobulin (33 kDa)

YKL-40 (40 kDa)

Immunoglobulin Free Light Chains (22.5 and 45 kDa)

More than the specific impact that each and every large middle molecule may have on the health of chronic kidney disease patients, it is critical to understand and address their collective effect. Uremia related to the retention of large middle molecules is indeed associated with inflammation and cardiovascular events.8,9,10

LARGE MIDDLE MOLECULES ARE ASSOCIATED WITH INFLAMMATION AND CARDIOVASCULAR EVENTS

A STEP CLOSER TOTHE NATURAL KIDNEYTURNING INNOVATIVE DESIGN INTO A CLINICAL SOLUTION

The THERANOVA dialyzer enables the HDx therapy by combining 4 therapeutic principles: permeability, selectivity, retention and internal filtration – into a single dialyzer design.

Its innovative medium cut-off (MCO) membrane expands the range of solutes removed during regular dialysis, while retaining essential proteins at a safe and controlled level. This unique cut-off and retention onset profile allows for filtration close to that of the natural kidney.4,5

HIGH-FLUXMEMBRANE GEOMETRY THERANOVA

Greater packing density

Smaller inner diameter and reduced wall thickness

190-215μm

30-50 μm

180μm

35 μm

Improved undulation

HIGHER PERMEABILITYWith an increased nominal pore size, the THERANOVA dialyzer has a significantly higher permeability for large middle molecules compared to regular high-flux membranes, before and after blood contact.

EFFECTIVE SELECTIVITY FOR LARGE PROTEINSBy combining a unique asymmetric 3-layer structure with a carefully controlled distribution of the pore size, the THERANOVA dialyzer enables a stable separation profile and selectivity throughout the treatment, keeping albumin removal at a controlled level.

Number of pores [a.u.]

Pore radius [nm]

2.0 4.0 6.0 8.0 12.010.0

High fl uxTHERANOVAHigh cut-off

0

Number of pores [a.u.]

Pore radius [nm]

2.0 4.0 6.0 8.0 12.010.0

High fl uxTHERANOVAHigh cut-off

0

A STEP CLOSER TO THE NATURAL KIDNEYBy expanding the range of solutes removed in dialysis, while retaining selectivity towards albumin and other essential proteins, the THERANOVA dialyzer is coming a step closer to the natural kidney.

0.6

0.8

1.0Sieving coeffi cient

Dextran molecular weight [g/mol]

0.4

0.2

0

104 105

Low-fl uxHigh-fl uxTHERANOVAGlomerular membrane

0.6

0.8

1.0Sieving coeffi cient

Dextran molecular weight [g/mol]

0.4

0.2

0

104 105

Low-fl uxHigh-fl uxTHERANOVAGlomerular membrane

A very thin inner layer (skin)

A sponge-like intermediate layer

THE MEMBRANE STRUCTURE IS ASYMMETRIC AND CAN BE SEEN IN CROSS SECTION AS THREE DISTINCT LAYERS:

A finger-like macro-porous outer layer

RETENTIONThe adsorption properties of the THERANOVA membrane maintain the same level of bacteria and endotoxin retention as other standard dialysis membranes.11 Despite its higher permeability, the THERANOVA membrane appears to be a safe and effective barrier to potential dialysis fluid contaminants. It is compatible with standard fluid quality (ISO 11663:2014) and does not require any additional fluid quality control measure.12

INTERNAL FILTRATIONThe inner diameter of the THERANOVA membrane has been carefully reduced in order to increase internal filtration along the membrane, conducive to an enhanced removal of large middle molecules.

TREATMENT EFFECTS AND THERAPY IMPLICATIONS (VS. HD)3

HD therapies have been the treatment of choice for many years — both for many patients and many clinics. The design and operating mode of the THERANOVA dialyzer enables the HDx therapy to be easily implemented on any HD monitor.13 This means by simply changing the dialyzer, any clinic can provide markedly greater clearances and intradialytic reduction ratios than regular HD – at ordinary blood flow rates.

EXPANDEDHEMODIALYSIS (HDx)

OVERALL CLEARANCE HDx VS. HDHDx with Theranova 400 dialyzer HD with latest generation high-flux dialyzer Qb = 300 ml/min – Treatment Time = 4 h (Mean) – n = 19

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

lambda free light chains45,000 Da

HD FX CORDIAX 80HDx THERANOVA 400 Standard error (SE)

*

*

* *

* *

* p < 0.001 vs high-fl ux HD

100

ml/min

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

lambda free light chains45,000 Da

HD FX CORDIAX 80HDx THERANOVA 400 Standard error (SE)

*

*

* *

* *

* p < 0.001 vs high-fl ux HD

100

ml/min

REDUCTION RATIO HDx VS. HDHDx with Theranova 400 dialyzer HD with latest generation high-flux dialyzer Qb = 300 ml/min – Treatment Time = 4 h (Mean) – n = 19

100

%

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

YKL-40

40,000 Da

lambda free light chains45,000 Da

Standard error (SE)HD FX CORDIAX 80HDx THERANOVA 400

** *

*

*

**

* p < 0.001 vs high-fl ux HD

100

%

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

YKL-40

40,000 Da

lambda free light chains45,000 Da

Standard error (SE)HD FX CORDIAX 80HDx THERANOVA 400

** *

*

*

**

* p < 0.001 vs high-fl ux HD

TREATMENT EFFECTS AND THERAPY IMPLICATIONS (VS. HDF)3

HDx therapy enabled by the THERANOVA dialyzer provides an equivalent removal of small and conventional middle molecules, with the possibility of greater removal for large middle molecules when compared to high-volume HDF. HDx performance can be achieved in all regular HD environments: this simplicity removes the potential burden of patient eligibility or therapy specific delivery systems.

EXPANDEDHEMODIALYSIS (HDx)

OVERALL CLEARANCE HDx VS. HDFHDx with Theranova 400 dialyzer HDF with latest generation high-flux dialyzer for HDF Qb = 400 ml/min – Treatment Time = 4.4 h – Vconv = 24L (Mean) – n = 20

100

ml/min

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

lambda free light chains45,000 Da

HDF post FX CORDIAX 800HDx with THERANOVA 400 Standard error (SE)

**

*

**

**

* p < 0.01 vs HDF ** p < 0.001 vs HDF

100

ml/min

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

lambda free light chains45,000 Da

HDF post FX CORDIAX 800HDx with THERANOVA 400 Standard error (SE)

**

*

**

**

* p < 0.01 vs HDF ** p < 0.001 vs HDF

REDUCTION RATIO HDx VS. HDFHDx with Theranova 400 dialyzer HDF with latest generation high-flux dialyzer for HDF Qb = 400 ml/min – Treatment Time = 4.4 h – Vconv = 24L (Mean) – n = 20

%

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

YKL-40

40,000 Da

lambda free light chains45,000 Da

Standard error (SE)HDF post FX CORDIAX 800HDx with THERANOVA 400

****

* *

*

**

100* p < 0.001 vs HDF ** p < 0.01 vs HDF

*** p < 0.05 vs. HDF

%

80

60

40

20

0beta 2

microglobulin 11,818 Da

myoglobin

17,000 Da

kappa free light chains22,500 Da

complement factor D

24,000 Da

alpha 1microglobulin

33,000 Da

YKL-40

40,000 Da

lambda free light chains45,000 Da

Standard error (SE)HDF post FX CORDIAX 800HDx with THERANOVA 400

****

* *

*

**

100* p < 0.001 vs HDF ** p < 0.01 vs HDF

*** p < 0.05 vs. HDF

ALBUMIN REMOVAL PER SESSION:

• 3 grams on average in all cases, limited to between 1 and 4 grams per treatment.• Similar removal compared to HDF on-line.• Does not seem to have any impact on serum albumin levels after 6 months compared to HDF.14

REMOVAL DURING CLINICAL TRIAL SESSIONS (IN GRAMS)

Qb = 300 mL/min Qb = 400 mL/min T = 4 h T = 4.4 h

Mean (± SD) 2.7±0.7 3.0±0.7

Median 2.9 3.2

Range 1.5-3.9 1.2-3.9

• Equivalent removal of small and conventional middle molecules.

• Greater removal possible for large middle molecules.• Applicable to all HD patients.

HDF PERFORMANCEAND BEYOND*

• HD infrastructure: no need for HDF capable monitors nor specific water quality and fluid quality assurance measures.15

• Avoid HDF additional running costs: disposable infusion line, use of larger amounts of dialysis water and concentrates.16

• Avoid requirement for specialist training and extensive monitoring during therapy delivery.17

AS SIMPLEAS HD

* Do not use THERANOVA dialyzers in HDF or HF mode

GLBL

/MG2

09/1

7-00

20 –

Feb

ruar

y 20

18

Baxter, Gambro, Making possible personal, MCO and Theranova

are trademarks of Baxter International Inc. or its subsidiaries.

Cordiax is a trademark of Fresenius Medical Care Deutschland GmbH.

Baxter Healthcare CorporationOne Baxter ParkwayDeerfield, IL 60015USA

MANUFACTURERGambro Dialysatoren GmbHHolger-Crafoord-Strasse 2672379 HechingenGermany

REFERENCES

1. Ronco C, et al. The rise of Expanded Hemodialysis. Blood Purif 2017; 44:I–VIII2. Hutchison CA, et al. The Rationale for Expanded Hemodialysis Therapy (HDx). Contrib Nephrol 2017; 191:142-523. Kirsch AH, et al. Performance of hemodialysis with novel medium cut-off dialyzers. Nephrol Dial Transpl 2017; 32(1):165-724. Boschetti-de-Fierro A, et al. MCO membranes: Enhanced Selectivity in High-Flux Class. Scientific Reports 2015; 5:184485. Zweigart C, et al. Medium cut-off membranes – closer to the natural kidney removal function. Int J Artif Organs 2017; 40(7):328-3346. Himmelfarb J, Ikizler TA. Hemodialysis. N Engl J Med 2010; 363(19):1833–18457. Chmielewski M, et al. The Peptidic Middle Molecules: Is Molecular Weight Doing the Trick? Sem in Nephro 2014; vol. 34, March, 118-348. Yilmaz MI, et al. Low-grade inflammation in chronic kidney disease patients before the start of renal replacement therapy: sources and consequences.

Clinical Nephro 2012; vol. 68, July, pp 1-99. Stenvinkel P, et al. Can treating persistent inflammation limit protein energy wasting? Sem in Dialysis 2012; vol. 26, January-February, pp 16-910. Akchurin OM, et al. Update on inflammation in chronic kidney disease. Blood Purif 2015; vol. 39, May, pp 84-9211. Schepers E, et al. Assessment of the association between increasing membrane pore size and endotoxin permeability using a novel experimental dialysis simulation set-up.

BMC Nephrology 2018; 19:112. Baxter. Theranova 400/500 Instructions For Use. N50 648 rev 003, 2017-05-2913. Baxter. Data on file. Theranova Limited Controlled Distribution Report 201614. Belmouaz M, et al. Comparison of hemodialysis with medium cut-off dialyzer and on-line hemodiafiltration on the removal of small and middle size moelcules.

Clinical Nephro 2018; 89 (1): 50-5615. Mazairac A, et al. The cost-utility of hemodiafiltration versus hemodialysis in the Convective Transport Study. Nephrol Dial Transplant; 28: 1865-187316. Baxter. Data on file. Therapy Cost Calculator 201617. Chapdelaine I, et al. Optimization of the convection volume in online post-dilution hemodiafiltration: practical and technical issues. Clin Kidney J 2015; 8: 191–198

For further information visit hdxtheranova.com:

These products meet the applicable provisions of Annex I (Essential Requirements) and Annex II (Full quality assurance system of the Council Directive 93/42/EEC of 14 June 1993, amended by Directive 2007/47/EC)