1 pda2007 fluid managment abu-alfa

8/2/2019 1 PDA2007 Fluid Managment Abu-Alfa

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Fluid Management in

Peritoneal Dialysis

Ali K. Abu-Alfa, MD, FASN

Associate Professor of MedicineDirector, Peritoneal Dialysis Program

Associate Director for outpatient Dialysis

Director of Clinical Trials

Yale School of Medicine

New Haven, Connecticuthttp://kidney.yale.edu


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Educational Objectives

Review physiology of ultrafiltration and impact of membranetransport characteristics.

Discuss fluid balance in PD with focus on clinical needs, goalsand effect on outcomes.

Identify areas of interventions for optimization of fluid removal.

Identify patients at risk for fluid retention.

Review role of alternative osmotic agents: Icodextrin.

Review ISPD guidelines and clinical algorithms for fluid

management in PD.


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Physiology of Ultrafiltration

Trans-capillary fluid movement:

Osmotic gradient (first and foremost).

Hydrostatic pressure (much less so).

Membrane function / surface area.

Lymphatic re-absorption.


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Physiology of Ultrafiltration:Structure of the Peritoneal Membrane


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Physiology of Ultrafiltration:Water, Glucose and Sodium Movements

Intercellular: 50%

Aquaporin mediated: 50%

CapillaryH2O

Peritoneal Space Glucose

Intercellular: >90%

Glucose transporter mediated:minimal

Na


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Physiology of Ultrafiltration:Sodium Sieving with 3.86% Dextrose Dialysate

LaMilia et al, Nephrol Dial Transplant (2004) 19: 1849-1855


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Physiology of Ultrafiltration:Effect of Sodium Sieving on Na Removal

Rodriguez-Carmona, PDI 2003 (22): 705-713.

0

50

100

150

200

250

Na removal

CAPDAPD

Icodextrin


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Physiology of Ultrafiltration:Crystalloid versus colloid osmosis

LaMilia et al, Nephrol Dial Transplant (2004) 19: 1849-1855

Blood in Peritoneal Capillaries

Dialysate filled Peritoneal Cavity

Endothelium

Mesothelium

ureacreatinine

glucose

macromolecules

crystalloidosmosis

colloidosmosis


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Physiology of Ultrafiltration:Crystalloid Osmosis

Daugirdas et al: Handbook of Dialysis, Third Edition, p 299, 2000

Normal serum osmolarity = 270 mOsm/L1

Dextrose Dialysate mOsm/L

1.36% 345

2.27% 395

3.86% 484


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-600

-400

-200

0

200

400

600800

-30 0 30 60 90 120 150 180 210 240

Time (min)

Cumulativetr

ansport(mL)

Absorption Transcapillary UF Net UF

Mactier RA, et al. J Clin Invest. 1987;80:1311-1316.

Physiology of Ultrafiltration:Net Ultrafiltration

UF: Ultrafiltration


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D/P: Dialysate / Plasma

L: Low Transporter

LA: Low Average Transporter

HA: High Average Transporter

H: High Transporter

Physiology of Ultrafiltration:Glucose Kinetics by Transport Status

0.2

0.3

0.40.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4

Hours

D/D0

Glucose L

LA

HA

H


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Data on file, courtesy of Baxter Healthcare Corporation.Data on file, courtesy of Baxter Healthcare Corporation.

Physiology of Ultrafiltration:Glucose Kinetics by Transport Status

-4-2

0

2

4

6

8

10

12

14

16

0 2 4 8 12

Dwell time (hr)

T

ranscap

illary

UF(mL/min)

200

250

300

350

400

450

500

O

smo

lari

ty(mosm

/kg

H2O)

Transcapillary UF Osmolarity


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Physiology of Ultrafiltration:Net Ultrafiltration: 1.36% Dextrose Dialysate

-800

-600

-400

-200

0

200

400

0 2 4 6 8 10 12 14 16Time (hr)

Low Low-Avg High-Avg High

CAPD

Overnight APDDaytime

NegativeUF

Hours

NetUF(ml)

Mujais S, Vonesh E. Kidney Int. 2002;62(suppl 81):S17-S22.


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CAPDOvernight

APD

Daytime

NegativeUF


-600

-400

-200

0200

400

600

800

0 2 4 6 8 10 12 14 16

Time (hr)

NetUF

(mL)

Low Low-Av Hi h-Av Hi h



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CAPDOvernight

APD

Daytime


-600

-200

200

600

1000

1400

1800

0 2 4 6 8 10 12 14 16

Time (hr)

Ne

tUF(m

L)




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Moberly J, Mujais S, et al. Kidney Int. suppl 81, Oct 2002

Physiology of Ultrafiltration:Glucose absorption: Caloric Cost

0

10

20

30

40

50

60

7080

90

Low Low Ave. High Ave. High

Peritoneal Transport Type

Glucoseab

sorbed

(g/8hrs) 1.36%

2.27%

3.86%

Widening differential


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Davies et al. J Am Soc Nephrol. 2001;12:1046-51

Physiology of Ultrafiltration:Changes in Transport Profile

30000

40000

5000060000

70000

Year 1 Year 2 Year 3 Year 4 Year 5

Group 1

Group 2

0.5

0.55

0.60.65

0.7

0.75

0.8

Start Year 1 Year 2 Year 3 Year 4 Year 5

Group 1

Group 2


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Role of Fluid Management in PD

Maintaining adequate fluid balance is an important

function of renal replacement therapy.

Achieving optimal fluid balance is a component of PD

adequacy.

Optimal fluid management plays a key role in patientoutcomes.


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Importance of Fluid Management

Reduction in Symptomatic Fluid Retention.

Blood pressure control: Preservation of Residual Renal Function.

Prevention or mitigation of Cardiovascular Disease

(IHD, LVH, CHF, CVA, PVD).

Reducing accelerated atherosclerosis process.

Prevention of symptoms simulating uremia.

Reduction in mortality.


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Symptomatic Fluid Retention (SFR)


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Symptomatic Fluid Retention

71 Episodes of SFR were identified in 66 PD patients.

High rates of non-compliance with dietary salt and fluidrestrictions as well as PD prescription were noted in the

SFR group when compared to a control group (149 pts).

Edema (100%), pulmonary congestion (80%) and

hypertension (83%) were the most commonmanifestations of SFR.

Tzamaloukas et al, JASN (6): 198-206, 1995.


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Prevalence of Hypertension in PD patients

Frankenfield DL, et al. Kidney Int. 1999;55:1998-2010.Cocchi R, et al. Nephrol Dial Transplant1999;14:1536-1540.

0

5

1 0

1 5

2 0

2 5

3 0

3 5

4 0

Nor m al H ig h -N o rma l

St ag e 1 St ag e 2 St ag e 3

JNC6 BP Cat eg or y

%

of

Patients

I t a l y

USA


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Fluid Removal and Sodium Restriction:Impact on Blood Pressure control

Gunal et al, AJKD (37): 588-193, 2001

47 hypertensive CAPD patients

Na Restriction (1.6 g/day for 4 weeks)

20 normotensive 27 hypertensive

Na Restriction and UF (3.86% use)3

normotensive

with enalapril

17 normotensive

4normotensive

with enalapril

7 hypertensive

3 hypertensive


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Fluid Removal:An Independent Predictor of Survival

Ates et al. Kidney Int. 2001, (60):767-776.


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Fluid Removal:Impact on Survival


Fluid Removal (mL/24 hr/1.73 m2)

Group I: 2035


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Sodium Removal:Impact on Survival


Sodium Removal (mmol/24 hr/1.73 m2)

Group I: 232


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Fluid Removal: UltrafiltrationA Predictor of Survival

Brown, et al. J Am Soc Nephrol. 2003;14:2948-2957.

Month

24181260

Proportion

Surviving

1.0

0.90.8

0.7

0.6

0.50.4

0.3

0.2

0.10.0

> 750 mL

< 750 mL

P= 0.005


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Fluid Removal: UltrafiltrationA Independent Predictor of Survival

Jansen, et al.Jansen, et al. Kidney Int.Kidney Int. 2005;68:11992005;68:1199--1205.1205.

1

2.29

3.09

1.7

3.41

0

1

2

3

4

=2.20Ultrafiltration (L/day)

Relative

RiskofDeath P = 0.04 for trend


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Fluid Removal: Urine VolumeA Predictor of Survival

Re-analysis of data from CANUSA study:

Effects of peritoneal and renal clearances on survival in601 patients

Addition of 24-hour urine volume as a time-dependent

covariate showed a marked association with therelative risk (RR) of death.

Each 250-mL increase in daily urine volume associated

with a 36% decrease in the RR of death (RR, 0.64;

95% CI, 0.51 to 0.80).

Bargman, et al. J Am Soc Nephrol. 2001;12:2158-2162.


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Fluid Removal:Areas of Intervention

Dietary Evaluation.

Residual renal function: Use of diuretics.

Use of ACEI and ARB to preserve RRF.

Compliance: Quality of life issues.

Characterization of edema : Leaks and hernias.

Catheter function and outflow obstruction.

Peritoneal UF profile: Optimizing Prescription.

Mujais, et al. Perit. Dial Int. 2000;20(suppl 4):S5-S21.


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Fluid Removal:Role of Diuretics

Medcalf J et al. Kidney Int. 2001;59:1128-1133.

61 CAPD patients new to dialysis randomized to furosemide 250

mg/day or control

Change in urine volume: +6.47 vs 23.3 mL/month (P= 0.047)

No effect on rate of decline of urinary solute clearances

Urine Volume (mL/24 hr)

7338401040Control

(n = 30)

107011961020Furosemide 250mg/day

(n = 31)

Month 12Month 6Baseline


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Preservation of Renal Function:Role of ACE Inhibitors

Li et al, Ann Intern Med. 2003;139:105-112.


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Preservation of Renal Function:Role of ARBs

Suzuki et al, Am J Kidney Dis43:1056-1064, 2004


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Fluid Management in PD:Negative UF with Lower Glucose Solutions

Wolfson, et al. Kidney Int. 2002;62(suppl 81):S46-S52

Woodrow, et al. Nephrol Dial Transplant. 1999;14:1530-1535Finkelstein, et al. J Am Soc Nephrol. 2005;16:546-554.

0

5

10

15

20

25

30

35

1.36%

Dextrose

2.27%

Dextrose

3.86%

Dextrose

Per

cen

to

fPa

tients

0

10

20

30

40

50

60

70

80

90

2.27%

Dextrose

3.86%

Dextrose

(All

Patients)

3.86%

Dextrose

(HA/H)

PercentofPatients


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Symptomatic Fluid Retention:Increased Risk in Patients with Higher Transport

0

10

20

30

40

50

Symptomatic Control

Percen

tofPatients

Low

Low-average

High-average

High

Tzamaloukas et al, JASN (6): 198-206, 1995.

Fl id M i PD N i UF


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Fluid Management in PD: Negative UFA Problem in HA/H Transport Patients

WolfsonWolfson, et al., et al. Am J Kidney DisAm J Kidney Dis. 2002;40:1055. 2002;40:1055--10651065Data on file, Baxter Healthcare Corporation. (courtesy)Data on file, Baxter Healthcare Corporation. (courtesy)

13.4

5.6

20.0 20.0

0

5

10

15

20

25

30

All Patients L/LA HA H

Perce

ntofPatients

WithN

egativeNetU

F

L: Low Transporter


HA: High Average TransporterH: High Transporter

PET Di t ib ti i N th A i


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PET Distribution in North America:Prevalence of HA/H Transport Patients

15%

37%

33%

15%

Low Low - Avg High- Avg High

Mujais S, et al. Kidney Int. Volume 62: s81, S17-S22, 2002

L: Low Transporter


HA: High Average TransporterH: High Transporter

D/P creatinine; N=1220.

Li it ti f D t f th L D ll


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Limitations of Dextrose for the Long Dwell

Increased risk of fluid absorption and diminished

or negative ultrafiltration

1-2

Reduced small solute clearance in high and high-

average transporters1-2

Possible adverse systemic metabolic effects from

increased glucose absorption1,3

Possible impact on peritoneal membrane functionof hypertonic glucose exposure3

1. Twardowski ZJ. Clinical Dialysis. 3rd ed. Appleton & Lange; 1995:322-342.

2. Mujais S, et al. Perit Dial Int. 2000;20:S5-S21.3. Mistry CD, Gokal R. Perit Dial Int. 1996;16:S104-S108.

Physiology of Ultrafiltration:


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Physiology of Ultrafiltration:Colloid Osmosis

Macromolecules with high reflection coefficients.

Isotonic with plasma.

Induces water transport across small intercellular pores.

Enhances UF with increased vascular surface area.

Maintains colloid osmotic pressure gradient for the

duration of the long dwell due to slow rate of absorptionvia the lymphatic system.

Avoids sodium sieving.

Physiologic example: albumin.

Availability for use in PD solutions: Icodextrin.

Colloid Osmosis:


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Colloid Osmosis:Source and Structure of Icodextrin

Corn Starch

Malto-Dextrin

Icodextrin

Enzymatichydrolysis

Membranefractionation

(14) chain

(16) branch

Colloid Osmosis:


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Colloid Osmosis:Pharmacokinetics of Icodextrin

Absorption:

Convective transport via lymphatic pathways

40% (60 g) absorbed during 12-hour dwell

Metabolism:

Metabolized by amylase to maltose

Predominantly in plasma; minimal peritoneal

Excreted by renal and dialytic clearance

Plasma levels:

Reach steady-state within 1 week of initiation Are stable during long-term therapy

Return to baseline within 7 days of discontinuation

Colloid Osmosis:


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Colloid Osmosis:Metabolism of Icodextrin

IcodextrinIcodextrin

OligosaccharidesOligosaccharides

(maltose)(maltose)

amylaseamylase

IntravascularIntravascularCompartmentCompartment

IntracellularIntracellularCompartmentCompartment

MaltoseMaltose

GlucoseGlucose

maltasemaltase


PeritonealPeritonealcavitycavity

Lymph

atic

Pathways

Metabolism of icodextrin to glucose occursMetabolism of icodextrin to glucose occurs

predominantly after absorption from the peritonealpredominantly after absorption from the peritoneal

cavity via lymphatic pathwayscavity via lymphatic pathways



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Physiology of Ultrafiltration:Mechanism of Action of Icodextrin

High reflection coefficient (size) of icodextrin underlies

colloid effects and sustains UF during long dwells

Peritoneal CavityPeritoneal Cavity InterstitiumInterstitium

Equal OsmolarityEqual Osmolarity

Fluid FlowFluid Flow

II

II

II

II

II

II

II



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Physiology of Ultrafiltration:UItrafiltration with 7.5% Icodextrin Solution

KredietKrediet RT. Table 5:RT. Table 5: Textbook of Peritoneal DialysisTextbook of Peritoneal Dialysis. 2. 2ndnd ed.ed. KluwerKluwerAcademic Publishers; 2000:135Academic Publishers; 2000:135--172.172.

Dex 105

Ico 12

Crystalloid

(mmHg)

Dex 486

Ico 285

305Osmolality

(mosm/kg H2O)

Dex 21

Ico 45

Dex 0.1

Ico 66

21Colloid

(mmHg)

9817Hydrostatic

(mmHg)

PressureGradient

DialysatePressure

CapillaryPressure

Colloid Osmosis with Icodextrin:


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Colloid Osmosis with Icodextrin:Maintenance of Osmotic Gradient:

0

20

40

60

80

100

0 2 4 6 8 10 12 14

Dwell time (hr)

Percent

Remainingin

Perito

nealCavity

Dextrose Icodextrin

UItrafiltration with 7.5% Icodextrin Solution:


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UItrafiltration with 7.5% Icodextrin Solution:Sustained UF Irrespective of Transport Status

-600

-200

200

600

1000

0 2 4 6 8 10 12 14 16

Time (hr)

NetU

F

(m


CAPD (night)CAPD (night)

APD (day)APD (day)

UF with 7.5% Icodextrin Solution:


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U t 5% code t So ut oComparison with 2.27% and 3.86% Solutions

-600

-400

-200

0

200

400

600

800

1000

0 2 4 6 8 10 12 14 16

Time (hr)

NetUF(mL)

2.27% Dextrose 3.86% Dextrose 7.5% Icodextrin

Mujais S, Vonesh E. Kidney Int. 2002;62(suppl 81):S17-S22Data on file, Baxter Healthcare Corporation. (courtesy)

CAPD (night)

APD (day)

Use of 7.5% Icodextrin for CAPD 8-16 hours Dwell :


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Comparison with 2.27% Dextrose Solution

Wolfson, et al. Am J Kidney Dis. 2002;40:1055-1065

328.7 332.9380

261.9

578.1605.8

0

100

200

300

400

500

600

700

Baseline Week 2 Week 4

LongDwell

NetUF(mL

2.27% Dextrose Icodextrin

Use of 7.5% Icodextrin for CAPD 8-16 hours Dwell:


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Wolfson, et al. Am J Kidney Dis. 2002;40:1055-1065

19

1513

20

20

0

5

10

15

20

25



PercentofPatientsWith

NegativeNetUF

(2.27% Dextrose)

Use of 7.5% Icodextrin for APD Long Dwell 12-16 hrs:


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Plum, et al.Am J Kidney Dis. 2002;39:862-871

-135 -165-175

206

-300

-200

-100

0

100

200

300

Baseline Week 12

LongDwe

llN

etUF(mL

)


gComparison with 2.27% Dextrose Solution

**PP


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7468 67 71

59

75

156 6

56

0

1020

304050

6070

8090

100

Baseline Week 1 Week 6 Week 12 Follow-up


***

**PP


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27.130

2528.9

33.3

0 0 00

10

20

30

40

50

Baseline Week 3 Week 12 Week 20


*

** PP


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High Transport Trial: Net UF

Finkelstein, Abu-Alfa et al. J Am Soc Nephrol2005;16:546-554

*P*P< 0.001 vs 3.86% dextrose (adjusted for baseline values).< 0.001 vs 3.86% dextrose (adjusted for baseline values).

0

100

200

300

400

500

600


Long

Dwel

lNe

tUF(mL)

**


(n=47)(n=47)

3.86% Dextrose3.86% Dextrose

(n=45)(n=45)

Use of 7.5% Icodextrin for APD Long Dwell:C i ith 3 86% D t S l ti


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High Transport Trial: % Patients with Negative UF

Finkelstein, Abu-Alfa et al. J Am Soc Nephrol2005;16:546-554

37.837.2 33.3

42.5

2.20

0

5

10

15

20

25

30

3540

45


3.86% Dextrose

Icodextrin

*P*P< 0.0001 vs 3.86% dextrose.< 0.0001 vs 3.86% dextrose.

**P

ercento

fPatientsWith

Nega

tiveNetUF

Use of 7.5% Icodextrin:Carbohydrate Absorption in HA/H Transport


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Carbohydrate Absorption in HA/H Transport

Mujais and Lin. Perit Dial Int. 2006;26(suppl 1):S4.

*P


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Effects on Plasma Glucose and Insulin Levels

GokalGokal, et al., et al. Kidney IntKidney Int. 2002;62(suppl 81):S62. 2002;62(suppl 81):S62--S71.S71.

0

20

40

60

80

100

0 2 4 8 12 16

Time (hr)

PlasmaInsulin(U/mL

)

0

2

4

6

8

10P

lasmaGlucos

e(mmol/L)

Insulin Glucose

Use of 7.5% Icodextrin:Icodextrin Skin Adverse Events


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Icodextrin Skin Adverse Events


*Some patients experienced more than one skin adverse event.*Some patients experienced more than one skin adverse event.

Exfoliative dermatitis

Skin disorder

Pruritus

Rash

0.3%1.8%

5.2%2.2%

6.6%5.5%

4.6%10.1%

Dextrose*

(n = 347)

Icodextrin*

(n = 493)

Usually occurred soon after icodextrin initiation (median:

3 weeks).

If rash occurs, icodextrin should be discontinued.

Use of 7.5% Icodextrin:Effect on Serum Sodium


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Predominantly due to dilutional effect of icodextrin

metabolites (osmotic effect).

Similar to hyponatremia related to hyperglycemia or

mannitol-like solutes in blood.

Not due to pseudohyponatremia.

Effect on Serum Sodium

Use of 7.5% Icodextrin:Glucose Monitor Interaction


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Maltose and/or icodextrin metabolites may interfere with

blood glucose determinations.1,2

Glucose monitors using dehydrogenase

pyrroloquinolinequinone (GDH PQQ) result in falsely

elevated glucose measurements in patients using

icodextrin.1

No interference noted with any other glucose assay

systems (eg, glucose oxidase, hexokinase).

GDH PQQ-based methods should not be used duringicodextrin therapy.

Glucose Monitor Interaction

11

WensWens, et al., et al. Perit Dial IntPerit Dial Int. 1998;18:603. 1998;18:603--609.609.22 DratwaDratwa, et al., et al. Perit Dial Int.Perit Dial Int. 1998;18(suppl 2):S85.1998;18(suppl 2):S85.

Use of 7.5% Icodextrin:Interaction with Amylase Assay


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Patients using icodextrin may experience a decline in

serum amylase activity.1

Decline likely related to interference of icodextrin

metabolites with the enzymatic-based amylase assay.2

Serum amylase assay should be used in patients on

icodextrin with full awareness of this interference.1

Serum lipase activity does not appear to be affected by

the presence of icodextrin and therefore may be an

adequate method to diagnose pancreatitis.

Interaction with Amylase Assay

1 Gokal, et al. Kidney Int. 2002;62(suppl 81):S62-S71.2 Schonicke, et al. J Am Soc Nephrol. 1999;10:229A.

Optimal Fluid Management:ISPD Guidelines


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ISPD Guidelines

Routine standardized monitoring and awareness of PETstatus

Dietary counseling of appropriate salt and water intake. Protection of Residual Renal Function (RRF).

Loop diuretics if RRF present.

Patient education for enhanced compliance.

Minimizing use of hypertonic glucose and monitoring forsuboptimal UF response as a warning sign for possibleultra-filtration failure.

Preservation of peritoneal membrane function. Hyperglycemia control.

Mujais, et al. Perit Dial Int. 2000;20(suppl 4):S5-S21Lo Wai-Kei et al: Perit Dial Int. 2006; 26: 520522

Therapeutic Goals: Rationale


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Hypertension in ESRD is predominantly volume-

dependent (salt sensitive).

Correction of volume expansion in most ESRD

patients leads to normalization of BP with limited

anti-hypertensive medications.

An edema-free state is a minimal requirement for

normovolemia, but does not ensure presence of

normovolemia

Therapeutic Goals:An Algorithm


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An Algorithm

Interventions

No

Monitor

Yes

NormotensionMinimize Drugs

Exception: Reno/

cardioprotective

Yes No

Edema Free

Exception: cardiomyopathy

Autonomic insufficiency

Abu-Alfa et al, Kidney Int (62), Suppl 81 (2002)

Interventions

Optimizing Prescription:Short and Long Dwells


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g

Abu-Alfa et al, Kidney Int (62), Suppl 81 (2002)

Increase

cycle number

Modify

tonicity

Increase

cycler time

Consider

fill volume

APD

Modify

tonicity

Increase

exchanges

Consider

fill volume

CAPD

Optimize

short dwell UF

Modifydwell time

Modify

tonicity

Alternateosmotic agent

Negative

net UF

Minimize3.86%

Positive

net UF

Evaluate

Long dwell UF

Summary


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Monitoring and managing fluid balance is important in PDpatients.

Attaining an edema-free state and normotension shouldbe the main therapeutic goals while minimizing need forhypertonic solutions.

Individualizing and separating the short and long dwellsdialysis prescriptions will enhance ultra-filtration andoverall fluid management.

Use of icodextrin helps enhance fluid removal whilereducing the need for hypertonic glucose solutions.

1 pda2007 fluid managment abu-alfa

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