safety and biocompatibility in perfect balance · safety and biocompatibility in perfect balance...

Safety and biocompatibility in perfect balance

Peritoneal Dialysis

balance_09.06_GB.qxd 27.09.2006 9:09 Uhr Seite U1

balance, the dual-chambered PD solution …

2

Glucose degradation products (GDPs) arise during

steam-sterilisation and storage of PD fluids.

Neutral pH and low GDPlevels

Reduces intraperitonealinflammation

Preserving peritonealcell functions

Preserving the peritoneal membrane

Utilising a dual-chambered bag allows the sterilisation

of the glucose to be performed at very low pH, thus

greatly reducing GDP formation.

balance minimises GDP formation


Minimising glucose degradation

3

The formation of GDP’s is pH dependent as demon-

strated by the example of 3-DG (3-deoxyglucosone) in

the figure below.

The graph clearly reveals that the lowest formation of 3-

DG is achieved at a pH value of around 3. This fact

also explains the higher amount of 3-DG in a double-

chamber bag containing a lactate and bicarbonate

buffered PD solution with the glucose sterilised at a

higher pH.1

� The sterilisation of glucose at a low pH (~3)

greatly reduces the formation of 3-DG and other

GDP’s in the balance PD solution (see figure).2

350

300

250

200

150

100

50

0

3-Deoxyglucosone

Acetaldehyde

Formaldehyde

Methylglyoxal

Low GDPs in balance

Con

cent

ratio

n (µ

mol

/L)

Lactate 35mM Lactate 35mM balance balancepH 5.5 pH 5.5 1.5% glucose 4.25% glucose

1.5% glucose 4.25% glucose

2 3 4 5 6

pH

140

120

100

80

60

40

20

0

Minimal GDP formation at low pH

balance

3-D

G (µ

mol

/L)

Low 3-DG content in balance

200

150

100

50

035mM lactateSterilisation ofglucose (2.3%)

at pH 3.0

15mM lactate/25mM bicarbonate

Sterilisation ofglucose (2.27%)

at pH 4.2

3-D

G (µ

mol

/L)

balance_09.06_GB.qxd 27.09.2006 9:09 Uhr Seite 3

Preserving peritoneal cell function

4

balance preserves cellular viability andfunction

Mesothelial cells (HPMC) were incubated with a con-

ventional PD fluid or with balance. The final pH of the

conventional PD fluid was adjusted to 7.3, both fluids

were changed every second day. These long-term in

vitro studies demonstrated higher viability of mesothe-

lial cells exposed to balance. Exposure to the conven-

tional PD fluid resulted in a significant reduction in cell

viability after just 3–5 days.

**

Results at day 7

Similar results were achieved on mesothelial cell func-

tion as measured by unchanged release of interleukin-6.3

In addition, balance causes less stress to the mesothe-

lial cells, as demonstrated by a minimal increase in

heat-shock-proteins (HSP-72).4

� balance features superior biocompatibility com-

pared to conventional PD fluid.

Conventional PDF

balance

p < 0.05*

150

125

100

75

50

25

0

HP

MC

via

bilit

y (%

of c

ontr

ol)

1.5% Glucose 4.25% Glucose

Preservation of cell viability with balance


Preserving the peritoneal membrane

5

balance reduces AGE formation

GDPs rather than glucose play a paramount role as

promotors for the formation of AGEs (advanced glyca-

tion end products), in particular 3-DG 5, 6, 7. Accu-

mulation of AGEs in the peritoneal membrane is asso-

ciated with increased permeability of the peritoneal

membrane and ultrafiltration reduction.8,9

Human serum albumin (HSA) was incubated with dif-

ferent commercially available PD solutions and a con-

trol solution. The formation of the AGE product CML

(Nε-(Carboxymethyl)lysine) was measured.

� In vitro AGE formation with balance is as low as

with sterile filtered control PD solution. 10

AGE formation is due to GDPs rather than high glucose concentration

Conventional PDF pH neutral; 4.25% glucose

Sterile filtered PDf pH neutral; 4.25% glucose (Control)

balance pH neutral; 4.25% glucose

1.0

0.8

0.6

0.4

0.2

0

0 10 20 30 40

Days of incubation

CM

L (u

nits

/mg

HS

A)


Less peritoneal damage by balance

6

Rats were exposed twice daily for six weeks to con-

ventional PD fluid or balance, both with 4.25% glucose

concentration. At the beginning and at the end of the

study a 4-hour dwell was performed to evaluate signs

of intraperitoneal inflammation. Additionally, after six

weeks, the rats were sacrificed and the peritoneal

membranes were histologically evaluated according to

a semiquantitative scale.

In rats treated with conventional PD fluid signs of

intraperitoneal inflammation did not change during the

study, whereas with balance the intensity of inflamma-

tion decreased (cell count, p<0.01; neutrophil/ macro-

phage ratio, p<0.05; hyaluronan, p<0.05).11

Less peritoneal fibrosis with balance

� Long-term exposure to balance causes less

peritoneal inflammation, less collagen synthe-

sis and less fibrosis in animals.

Lightmicroscopy, semiquantitive scale:

• peritoneal thickening• presence of the peritoneal stratification• presence of neovascularisation

p < 0.05

Conventional balancePDF

8

7

6

5

4

3

2

1

0

Mic

rosc

opic

sca

le


Less vasodilation with balance

7

Intravital microscopy was used to analyse the vasoactive

effects of different commercially available PD solutions

on the rat peritoneal membrane. A conventional, acidic

pH, lactate buffered 4.25% glucose PD fluid induced

maximal vasodilation of the mesenteric arteries, resulting

in a doubling of the arteriolar flow and an increase in

capillary recruitment. The balance solution only induced

a transient vasodilatory effect, thereby potentially delay-

ing the development of vascular sclerosis.

With balance no persistent vasodilation and consecutive maximal arteriolar flow

This development is seen in patients long time on PD

and maybe based on continuous elevations of vascu-

lar flow as seen with conventional PD fluids.

� balance has minimal effect on vasoregulation

and thus helps to preserve the peritoneal func-

tion and longevity. 12

Control

1.5% Glucose

4.25% Glucose

Baseline

Dialysate

B=

D=

Time (min) B0 D2 D10 D20 B10 Time (min) B0 D2 D10 D20 B10

Conventional PDF balance

200

150

100

50

0

200

150

100

50

0

Art

erio

lar

flow

(% o

f bas

elin

e va

lues

)

Art

erio

lar

flow

(% o

f bas

elin

e va

lues

)


European Balance Trial EBT

8

The European Balance Trial was performed to see the

effects of balance on the peritoneal membrane of

CAPD patients. This open, controlled and randomised

study took place in 23 centres in Europe. Prior to entry

into the study patients had been on PD for at least 3

but not longer than 18 months.13

Preliminary results show a 3–4 fold increase in effluent

CA125, a reported marker of mesothelial cell mass and

turnover14,15, in patients treated with balance. Following

a switch to conventional PD solution CA125 levels

return to baseline. The potential of a local membrane

protective effect of balance is clearly demonstrated.

Euro Balance Trial

Run-in-Phase Treatment Phase I Treatment Phase II

1 month 3 months 3 months

Conventional PDF balance

PatientGroup I

PatientGroup II

� Increased CA125 levels with balance indicate

improved mesothelial cell integrity.

Hyaluronic acid (HA), also released by mesothelial cells,

and reported to reflect intraperitoneal inflammation 16,

was greatly decreased in both patient groups when

treated with balance. This result clearly indicates the

reduction of intraperitoneal inflammation.

� Lowered hyaluronic acid using balance clearly

indicates reduction of intraperitoneal inflam-

mation.

balance Conventional PDF

100

80

60

40

20

0

120

100

80

60

40

20

00 3 6 0 3 6

(U/m

l)

(U/m

l)

CA125-values in patient effluate

ns p < 0.001

Month Month

p < 0.001 p < 0.001

Boxplots andmedian

Patient Group I (n = 36) Patient Group II (n = 35)

balance Conventional PDF

Hyaluronic acid in effluate reduced with balance

Patient Group I (n = 36) Patient Group II (n = 35)

p < 0.01 p = 0.02 p = 0.03ns

0 3 6Month

0 3 6Month

(ng/

ml)

(ng/

ml)

1500

1000

500

0

1500

1000

500

0

Boxplots and median


Reduced systemic AGE formation with balance

9

During a three month treatment with balance imida-

zolon, a prominent AGE product was significantly

reduced in the serum in both patient groups, which

may be the result of less carbonyl compounds (GDPs)

in the dialysate.

Conclusions

Characterised by a neutral pH and low GDPs

balance promises to better preserve peritoneal

membrane function by reduced inflammatory

potential, minimal vasoreactive effects and less

mesothelial damage.

A potential for preserving peritoneal function and

longevity is suggested.

� The low GDP PD solution balance leads to a

significant reduction of AGE-formation in the

serum.

Boxplots and median

Boxplots and median

Reduced systemic AGE formation with balance

30

20

10

0

(µg/

ml)

0 3 6

Month

0 3 6

Month

30

20

10

0

(µg/

ml)

balance

Conventional PDF

p = 0.01 p = 0.01 p = 0.02

Patient Group I (n = 20) Patient Group II (n = 11)Imidazolone in the serum


The details make the difference

10

Easy handling with DISC and PIN technology

This has greatly simplified patient handling and signifi-

cantly improved the safety of bag exchanges. The

patient regulates all treatment steps by turning the

switch on the DISC. The automatic closing of the sys-

tem via the PIN technology protects the patient from

external contamination.

The pH-neutral mix

The new balance solution is presented in a double

chamber bag, separated by a λ-shaped seam. The

solution containing glucose has a very low pH value

(approx. 3.1) to reduce the generation of GDPs during

sterilisation. The other compartment contains the buffer

and has a pH of approx. 8.0. By mixing the two solu-

tions, the patient obtains a pH-neutral fluid that is

almost free of GDPs.

Ecologically friendly Biofine®

balance solution is presented in PD systems compris-

ing Biofine® material. Biofine® is a non-PVC substance

composed of polyolefines, developed by Fresenius

Medical Care. This material has proved to be an excel-

lent barrier to water vapour and thus guarantees con-

sistency of the solution during the entire storage peri-

od. After product assembly and sealing within the outer

wrapping the complete system is sterilised at 121°C.

This ensures that all parts within the outer wrap are

sterile.

� balance adds new improvements to the already

successful stay•safe® system. Every detail has

been carefully studied and optimised to deliver

the maximum benefit in terms of safety, bio-

compatibility and ease of use.


References

11

1 Zimmeck T, Tauer A, Fuenfrocken M, Pischetsrieder M. How to reduce3-deoxyglucosone and acetaldehyde in peritoneal dialysis fluids. PeritDial Int. 2002;22(3): 350-6.

2 Tauer A, Schmitt R, Knerr T, et al. Formation of the glucose degradationproduct 3-deoxyglucosone and other carbonyl-compounds in single- ordouble-chamber peritoneal dialysis fluids. Perit Dial Int. 2000;20:142.

3 Witowski J, Bender TO, Wisniewska-Elnur J, et al. Mesothelial toxicityof peritoneal dialysis fluids is related primarily to glucose degradationproducts, not to glucose per se. Perit Dial Int. 2003;23(4):381-90.

4 Arbeiter K, Bidmon B, Endemann M, et al. Peritoneal dialysate fluidcomposition determines heat shock protein expression patterns inhuman mesothelial cells. Kidney Int. 2001;60:1930-7.

5 Niwa H, Takeda A, Wakai M, et al. Accelerated formation of N epsilon-(carboxymethyl) lysine, an advanced glycation end product, by glyoxaland 3-deoxyglucosone in cultured rat sensory neurons. BiochemBiophys Res Commun. 1998;248:93-7.

6 Lamb EJ, Cattell WR, Dawnay AB. In vitro formation of advanced glycationend products in peritoneal dialysis fluid. Kidney Int. 1995;47:1768-1774.

7 Schalkwijk CG, Posthuma N, ten Brink HJ, ter Wee PM, Teerlink T.Induction of 1,2-dicarbonyl compounds, intermediates in the formationof advanced glycation end-products, during heat-sterilization of glu-cose-based peritoneal dialysis fluids. Perit Dial Int. 1999;19:325-333.

8 Nakayama M, Kawaguchi Y, Yamada K, et al. Immunohistochemicaldetection of advanced glycosylation end-products in the peritoneumand its possible pathophysiological role in CAPD. Kidney Int.1997;51:182-6.

9 Honda K, Nitta K, Horita S, Yumura W, Nihei H, Nagai R, Ikeda K,Horiuchi S. Accumulation of advanced glycation end products in theperitoneal vasculature of continuous ambulatory peritoneal dialysispatients with low ultrafiltration. Nephrol Dial Transplant. 1999;14:1541-9.

10 Tauer A, Knerr T, Niwa T, et al. In vitro formation of Nε-(Carboxymethyl)-lysine and imidazolones under conditions similar to continuous ambula-tory peritoneal dialysis. Biochem Biophys Res Commun.2001;280:1408-14.

11 Wieczorowska-Tobis K, Polubinska A, Schaub T P, et al. Influence ofneutral-pH dialysis solutions on the peritoneal membrane: a long-terminvestigation in rats. Perit Dial Int. 2001;21 Suppl 3:S108-13.

12 Mortier S, De Vriese AS, Van De Voorde et al. Hemodynamic effects ofperitoneal dialysis solutions on the peritoneal membrane: Role of acidity,buffer choice, glucose concentration, and glucose degradation prod-ucts. J Am Soc Nephrol. 2002;13:480-9.

13 Williams JD, Topley N, Craig KJ, Mackenzie RK, Pischetsrieder M, LageC, Passlick-Deetjen J, on behalf of the Euro Balance Trial group. TheEuro-Balance Trial: The effect of a new biocompatible peritoneal dialysisfluid (balance) on the peritoneal membrane. Kidney International in press.

14 Krediet RT. Dialysate cancer antigen 125 concentration as marker ofperitoneal membrane status in patients treated with chronic peritonealdialysis. Perit Dial Int. 2001;21:560-7.

15 Visser CE, Brouwer-Steenbergen JJ, Betjes MG, et al. Cancer antigen125: a bulk marker for the mesothelial mass in stable peritoneal dialysispatients. Nephrol Dial Transplant. 1995;10:64-9.

16 Yung S, Coles GA, Williams JD, et al. The source and possible significanceof hyaluronan in the peritoneal cavity. Kidney Int. 1994;46(2):527-33.


Fresenius Medical Care Deutschland GmbH · 61346 Bad Homburg v. d. H. · Germany · Phone: +49 (0) 6172-609-0 · Fax: +49 (0) 6172-609-2191Head office: Else-Kröner-Straße 1 · 61352 Bad Homburg v. d. H. · Germany

www.fmc-ag.com

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Information

balance 1.5% glucose, 1.75 mmol/L calcium, solution for peritoneal dialysisbalance 2.3% glucose, 1.75 mmol/L calcium, solution for peritoneal dialysisbalance 4.25% glucose, 1.75 mmol/L calcium, solution for peritoneal dialysisbalance 1.5% glucose, 1.25 mmol/L calcium, solution for peritoneal dialysisbalance 2.3% glucose, 1.25 mmol/L calcium, solution for peritoneal dialysisbalance 4.25% glucose, 1.25 mmol/L calcium, solution for peritoneal dialysis

Composition: 1 litre of the neutral ready-to-use solution contains:

Active substances balance balance balance balance balance balance(g/L) 1.5% glucose 2.3% glucose 4.25% glucose 1.5% glucose 2.3% glucose 4.25% glucose

1.75 mmol/L calcium 1.75 mmol/L calcium 1.75 mmol/L calcium 1.25 mmol/L calcium 1.25 mmol/L calcium 1.25 mmol/L calcium

Sodium chloride 5.640 5.640 5.640 5.640 5.640 5.640Sodium lactate 3.925 3.925 3.925 3.925 3.925 3.925(as sodium lactate solution)Calcium chloride 2H2O 0.2573 0.2573 0.2573 0.1838 0.1838 0.1838Magnesium chloride 6H2O 0.1017 0.1017 0.1017 0.1017 0.1017 0.1017Anhydrous glucose 15 22.73 42.5 15 22.73 42.5(as glucose monohydrate)

Active substances (mmol/L)Na+ 134 134 134 134 134 134Ca2+ 1.75 1.75 1.75 1.25 1.25 1.25Mg2+ 0.5 0.5 0.5 0.5 0.5 0.5Cl– 101.5 101.5 101.5 100.5 100.5 100.5Lactate 35 35 35 35 35 35Theoretical osmolarity (mosm/L) 358 401 511 356 399 509

Excipients: Water for injections, hydrochloric acid, sodium hydroxide, sodiumhydrogen carbonate.

Indications: End-stage (decompensated) chronic renal failure of any origin treat-ed with peritoneal dialysis.

Contraindications: Solution related: Solutions with 1.5%/2.3%/4.25% glucose,1.75 mmol/L calcium: Severe hypokalaemia and severe hypercalcaemia.Solutions with 1.5%/2.3%/4.25% glucose, 1.25 mmol/L calcium: Severehypokalaemia and severe hypocalcaemia. Solutions with 4.25% glucose: Addi-tionally hypovolaemia and arterial hypotension. Treatment related: Recentabdominal surgery or injury, burns, hernia, inflammatory abdominal skin reaction(dermatitis), inflammatory bowel diseases (Crohn’s disease, ulcerative colitis,diverticulitis), peritonitis, non-healing weeping wounds (abdominal fistulae), intra-abdominal tumours, intestinal obstruction (ileus), lung diseases (especially pneu-monia), metabolic disorders (lactic acidosis), generalised blood poisoning (sep-sis), extreme weight loss (cachexia), particularly when adequate nutrition isimpossible, in cases of accumulation of uraemic toxins in the blood (uraemia) theelimination of which can not be managed by peritoneal dialysis, very high levelsof fat in the blood (hyperlipidaemia).

Undesirable effects: Infections: Peritonitis (very common); skin exit site andtunnel infections (very common); in very rare cases sepsis. Disorders of the hor-mone balance for solutions containing 1.25mmol/L calcium: Overactivity of theparathyroid gland with potential disorders of the bone metabolism. Metabolismand nutrition disorders: Increased blood sugar and fat levels; increase in bodyweight due to the continuous uptake of glucose from the peritoneal dialysis solu-tion. Cardiac and vascular disorders: Frequent pulse; decreased or increasedblood pressure. Respiratory disorders: Shortness of breath due to elevation ofthe diaphragm, shoulder pain. Gastrointestinal disorders: Diarrhoea; constipa-tion; hernia (very common); abdominal distension and sensation of fullness.Renal disorders: Electrolyte disturbances, e.g. decreased potassium levels (very

common), increased calcium levels in combination with an increased calciumuptake, e.g. by the administration of calcium containing phosphate binders ordecreased calcium levels for solutions containing 1.25mmol/L calcium. Generaldisorders and administration/catheter site conditions: General malaise; redness,swellings, exudations, crusts and pain at the catheter exit site; dizziness; oede-ma; disturbances in hydration indicated either by a rapid decrease (dehydra-tion) or increase (overhydration) in body weight. Severe dehydration might occurwhen using solutions of higher glucose concentration. Peritoneal dialysis pro-cedure related disorders: Cloudy effluent; in- and outflow disturbances of thedialysis solution.

Drug Interactions: The use of these peritoneal dialysis solutions can lead to aloss of efficacy of other medicinal products if these are dialysable through theperitoneal membrane. A dose adjustment might be necessary. The frequency ofdigitalis-associated adverse drug reactions can be increased due to reducedserum potassium levels. The use of diuretic agents may result in water and elec-trolyte imbalances. In diabetic patients the daily dose of insulin or oral hypogly-caemic medicinal products must be adjusted to take account of the increasedglucose load. For solutions containing 1.75 mmol/L calcium the concomitantadministration of calcium-containing medicinal products or vitamin D may causehypercalcaemia.

Warnings and Precautions: Do not use unless solution is clear and containerundamaged. For single use only. Any unused portion of the solution is to be dis-carded. Do not use before mixing both solutions. Do not store below 4°C. Keepout of the reach and sight of children.

Date: December 2005

Fresenius Medical Care Deutschland GmbH61346 Bad Homburg, Germany

These solutions are delivered in a double chamberbag. One chamber contains the alkaline lactate solution, the other chamber contains the acidic glucose-based electrolyte solution. Mixing of bothsolutions by opening the middle seam between thetwo chambers results in the neutral ready-to-usesolution.


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