Nuevas Soluciones en DP, Sirven?

Prueba en diabéticos con transporte peritoneal alto y promedio alto

Nuevas Soluciones en DP, Sirven?

Prueba en diabéticos con transporte peritoneal alto y promedio alto

Dr. José Ramón Paniagua SierraUnidad de Investigación Médica en Enfermedades Nefrológicas. UMAE HE CMN S XXI, México, D. F.

Dr. José Ramón Paniagua SierraUnidad de Investigación Médica en Enfermedades Nefrológicas. UMAE HE CMN S XXI, México, D. F.

Background

Sodium intake and extracellular fluid volume expansion have been associated with hypertension and cardiovascular mortality in the general population

Extracellular fluid volume expansion is the most frequent cause of hypertension in ESRD patients with or without dialysis treatment. It has been related with other predictors of death like left ventricular hypertrophy

Extracellular fluid volume expansion has also been related with lost of RRF and low grade chronic inflammation

Sodium intake and extracellular fluid volume expansion have been associated with hypertension and cardiovascular mortality in the general population

Extracellular fluid volume expansion is the most frequent cause of hypertension in ESRD patients with or without dialysis treatment. It has been related with other predictors of death like left ventricular hypertrophy

Extracellular fluid volume expansion has also been related with lost of RRF and low grade chronic inflammation

Background

Several clinical conditions and serum markers are now known as predictors of clinical outcomes in ESRD patients. Among them: Diabetes Cardiovascular morbidity (LVH, HT, proBNP, TNt) Malnutrition (SA, TF, LBM, TBW, MAC) Inflammation (CRP, TNF, IL-6) Fluid and sodium removal

The variety of predictors suggest a complex network of interactions between them. ECFv expansion may have a significant role

Several clinical conditions and serum markers are now known as predictors of clinical outcomes in ESRD patients. Among them: Diabetes Cardiovascular morbidity (LVH, HT, proBNP, TNt) Malnutrition (SA, TF, LBM, TBW, MAC) Inflammation (CRP, TNF, IL-6) Fluid and sodium removal

The variety of predictors suggest a complex network of interactions between them. ECFv expansion may have a significant role

ADEMEX Mortality ADEMEX Mortality

IL 6 and mortalityIL 6 and mortality

C-reactive protein and mortality

Fluid removal and mortality

pBNP and mortality

Relationship of inflammation, ECFv and DM

MALNUTRITIONOR WASTING

MALNUTRITIONOR WASTING

INFLAMMATIONINFLAMMATION CV DISEASECV DISEASE CV DEATHCV DEATH

Relationship of inflammation,ECFv and DM

MALNUTRITIONOR WASTING

MALNUTRITIONOR WASTING

INFLAMMATIONINFLAMMATION CV DISEASECV DISEASE CV DEATHCV DEATH

ECFvEXPANSION

ECFvEXPANSION

PERITONEALPERMEABILITYPERITONEAL

PERMEABILITY PRESSURE VOLUME

PRESSURE VOLUME

Relationship of inflammation, ECFv and DM

MALNUTRITIONOR WASTING

MALNUTRITIONOR WASTING

INFLAMMATIONINFLAMMATION CV DISEASECV DISEASE CV DEATHCV DEATH

ECFvEXPANSION

ECFvEXPANSION

PERITONEALPERMEABILITYPERITONEAL

PERMEABILITY PRESSURE VOLUME

PRESSURE VOLUME

D MCHO-PTG

D MCHO-PTG

? ?

Background

The success in the control of ECFv of PD patients depends on:

Sodium and fluid intake Residual renal function Peritoneal transport type (PET) Type and concentration of the osmotic agent in the

dialysis solution

The success in the control of ECFv of PD patients depends on:

Sodium and fluid intake Residual renal function Peritoneal transport type (PET) Type and concentration of the osmotic agent in the

dialysis solution

BackgroundBackground

Glucose is the most commonly used osmotic agent. Disadvantages:

Damage of mesothelial cells by glucose degradation products and advanced glycation products

Peritoneal glucose absorption. Then: Loss of osmotic gradient = deficient UF Obesity, low protein intake, impairment in metabolic

control

Diabetes increases glucose disadvantages

Glucose is the most commonly used osmotic agent. Disadvantages:

Damage of mesothelial cells by glucose degradation products and advanced glycation products

Peritoneal glucose absorption. Then: Loss of osmotic gradient = deficient UF Obesity, low protein intake, impairment in metabolic

control

Diabetes increases glucose disadvantages

IcodextrinIcodextrin

It has been successfully used as osmotic agent, particularly in high transporters

It does not have the glucose disadvantages

It has been successfully used as osmotic agent, particularly in high transporters

It does not have the glucose disadvantages Chain α (1→4)

Chain α (1→6)

Background Background

In spite of the potential benefits of icodextrin in increasing ultrafiltration without metabolic disadvantages in high-transport diabetic PD patients, RCT are not available

Information is important for populations with high rates of diabetics in their PD programs. This is the case of Mexico and other countries.

In spite of the potential benefits of icodextrin in increasing ultrafiltration without metabolic disadvantages in high-transport diabetic PD patients, RCT are not available

Information is important for populations with high rates of diabetics in their PD programs. This is the case of Mexico and other countries.

Objective Objective

Primary outcomes: Improvement in

peritoneal UF Reduction of ECFv Control of BP, edema

and CV function Metabolic control

Primary outcomes: Improvement in

peritoneal UF Reduction of ECFv Control of BP, edema

and CV function Metabolic control

Secondary outcomes: Nutrition improvement Control of inflammation Quality of life Mortality

Secondary outcomes: Nutrition improvement Control of inflammation Quality of life Mortality

To test the clinical usefulness of icodextrin based solution in high transport diabetic patients in PDTo test the clinical usefulness of icodextrin based solution in high transport diabetic patients in PD

Study designTarget of treatment

Study designTarget of treatment

To reach control of blood pressure and edema through the increment in peritoneal ultrafiltration

Treatments. 3x2L, 1.5% glucose exchanges plus: Control group: Glucose-based solutions, at least 1 bag

with 2.5% glucose in the longest dwell Icodextrin group: Icodextrin-based solution (7.5%) in the

longest dwell Replacement of 1.5% for 2.5 or 4.25% glucose was

allowed to reach the treatment goal

To reach control of blood pressure and edema through the increment in peritoneal ultrafiltration

Treatments. 3x2L, 1.5% glucose exchanges plus: Control group: Glucose-based solutions, at least 1 bag

with 2.5% glucose in the longest dwell Icodextrin group: Icodextrin-based solution (7.5%) in the

longest dwell Replacement of 1.5% for 2.5 or 4.25% glucose was

allowed to reach the treatment goal

Study designStudy design

Randomized clinical trial

Open label Multicentric (HGZ 8; HGZ 25; HGZ 27; HGZ 47. IMSS,

México, D. F.) Central randomization Central laboratory (UIMEN) Follow-up: 6 months; 12 months

Randomized clinical trial

Open label Multicentric (HGZ 8; HGZ 25; HGZ 27; HGZ 47. IMSS,

México, D. F.) Central randomization Central laboratory (UIMEN) Follow-up: 6 months; 12 months

Inclusion criteria Diabetics Adults High and high average

transport Without selection by

gender or time on dialysis

No inclusion criteria Seropositivity HB, HIV CA, immunosuppression

Inclusion criteria Diabetics Adults High and high average

transport Without selection by

gender or time on dialysis

No inclusion criteria Seropositivity HB, HIV CA, immunosuppression

Exclusion criteria Patient decision Medical decision Transplant Change of address

Exclusion criteria Patient decision Medical decision Transplant Change of address

Material and methodsPatients

ResultsResults

Without differences between groups at baseline in:

Age Gender Blood pressure Body composition Dialysis adequacy Biochemical parameters Comorbidity

Without differences between groups at baseline in:

Age Gender Blood pressure Body composition Dialysis adequacy Biochemical parameters Comorbidity

Results

Prescription In the control group two thirds of the patients needed more

than one bag of 2.5% glucose or at least one bag of 4.25% glucose. In the icodextrin group only 9% needed a bag with more than 1.5% of glucose

Prescription In the control group two thirds of the patients needed more

than one bag of 2.5% glucose or at least one bag of 4.25% glucose. In the icodextrin group only 9% needed a bag with more than 1.5% of glucose

0 3 6 9 12

0

20

40

60

80

100GLU >1 bag 2.5% glucose

ICO > bag 2.5% glucose

GLU > 1 bag 4.25% glucose

ICO > 1 bag 4.25% glucose

Months

% P

atie

nts

ResultsActual prescription

Results

Metabolic control

Results

0 3 6 9 12

-100

-80

-60

-40

-20

0GLU

ICO

+p<0.01 ICO vs GLU

+ + + + + + + + + ++ + +

Months

G

luco

se e

xpo

sure

(g/d

)

Results

0 3 6 9 12

-100

-80

-60

-40

-20

0GLU

ICO

+p<0.01 ICO vs GLU

++

+ + + + + ++

Months

G

luco

se a

bso

rpti

on

(g/d

)

Mean±EEM*p<0.05; ** p<0.03; *** p<0.01 vs Control‡p<0.05; ‡ ‡ p<0.03; ‡ ‡ ‡ p<0.01 vs Basal

Mean±EEM*p<0.05; ** p<0.03; *** p<0.01 vs Control‡p<0.05; ‡ ‡ p<0.03; ‡ ‡ ‡ p<0.01 vs Basal

0 3 6 9 12

-5-4-3-2-10123456

GLU

ICO

A

GBS vs IBS p<0.001

Months

B

od

y w

eig

ht

(kg

)

Results

Results

0 3 6 9 12

-100

-75

-50

-25

0

25

50

75

100GLU

ICO

A

* p<0.05 IBS vs GBS

**

Months

F

asti

ng

ser

um

Glu

cose

(m

g/d

L)

0 3 6 9 12

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0GLU

ICO

C

* p<0.05 IBS vs GBS+p<0.01 IBS vs GBS

* *

+

+

Months

H

b a

1c (

%)

Results

0 3 6 9 12

-15

-10

-5

0

5

10GLU

ICO

C

* p<0.05 IBS vs GBS+p<0.01 IBS vs GBS

+++

++++**

*

Months

I

nsu

lin

do

se (

U/d

)

Results

0 3 6 9 12

-200

-150

-100

-50

0

50

100GLU

ICO

B

* p<0.05 IBS vs GBS+p<0.01 IBS vs GBS

+

+

Months

S

eru

m T

rig

lyce

rid

es(m

g/d

L)

Results

3 6 9 12

-0.4

-0.3

-0.2

-0.1

-0.0

0.1

0.2

0.3

0.4CtrIco

Months

n

PC

R (

g/k

g/2

4 h

r)

Results

Results

Body fluids and cardiovascular parameters

ResultsUltrafiltration

0 3 6 9 12

-800

-600

-400

-200

0

200

400GLUICO

GBS vs IBS p<0.006

Months

U

ltra

filt

rati

on

(m

L/d

)

Results

0 3 6 9 12

-8

-7

-6

-5

-4

-3

-2

-1

0

1GLU TBW

ICO TBW

GLU ECFv

ICO ECFv

B

Months

B

od

y fl

uid

s (L

)

ResultsBP (in office)

0 3 6 9 12

-25-20-15-10

-505

10152025

GLU systolic BP

ICO systolic BP

GLU diastolic BP

ICO diastolic BP

* p<0.05 IBS vs GBS+p<0.01 IBS vs GBS+ +

+ + +

+++ + + + *

A

Months

B

loo

d p

ress

ure

(mm

Hg

)

ResultsBP (ambulatory)

0 6 12

-30

-20

-10

0

10GLU

ICO

Months

S

BP

-day

(m

mH

g)

**

**

0 6 12

-10

-5

0

5

10GLU

ICO

Months

D

BP

-day

(m

mH

g)

** *

0 6 12

-30

-20

-10

0

10GLU

ICO

Months

S

BP

-nig

ht

(mm

Hg

)

***

0 6 12

-10

-5

0

5

10GLU

ICO

Months

D

BP

-nig

ht

(mm

Hg

)**

****

**

*= p<0.05 vs basal; **= p<0.01 vs basal; = p<0.05 vs glucose group; = p<0.01 vs glucose group

ResultsEKG basal

Parameter

Glucose

Icodextrin

p

Heart rate (beats/min) 79.4 ± 8.3 78.9 ± 5.9 0.31 In office Systolic BP (mmHg) 139.8 ± 29.4 148.9 ± 24.1 0.20 In office diastolic BP (mmHg) 80.2 ± 16.4 84.9 ± 15.0 0.27 Cardiothoracic ratio (%) 49.8 ± 6.3 49.6 ± 6.4 0.75 LVEDD (mm) 48.2 ± 6.7 49.2 ± 5.8 0.53 IVS thickness (mm) 1.20 ± 0.40 1.20 ± 0.29 0.59 Posterior wall thickness (mm) 1.22 ± 0.30 1.22 ± 0.26 0.38 LVM (g) 266 ± 82 279 ± 83 0.71 Ejection fraction (%) 59.2 ± 12.3 60.3 ± 10.0 0.93 Fractional shortening (%) 32.8 ± 7.5 32.9 ± 5.8 0.56 E:A wave ratio 0.75 ± 0.47 1.07 ± 0.75 0.40 Inferior vena cava diameter (mm) 12.7 ± 4.4 14.5 ± 5.3 0.27 LF (0.05-0.15 Hz) 28.3 ± 14.1 29.8 ± 13.9 0.45 HF (0.15-0.40 Hz) 25.5 ± 16.4 25.7 ± 15.2 0.41 NT-pro-BNP (mL) 5.1 ± 2.5 4.8 ± 2.0 TNT (mL) 2.13 ± 2.57 2.11 ± 1.80

Values are mean ± SD or *= frequencies; **= median ? interquartile range; BP= blood pressure; LVEDD= left ventricular end diastolic diameter; IVD= interventricular septum; LVM= left ventricular mass; LF= power in the low frequency domain; HF= powering the high frequency domain; P values are based on the Student t test, Wilcoxon rank-sum test, or 2 tests according to the variable characteristics

ResultsEKG changes

Parameter

Group

Baseline

6 months from baseline

(n=23, 20)

12 months from baseline

(n=26, 19) Glucose 0.0 -3.1 ± 6.6* -3.2 ± 9.1* LVEDD (mm) Icodextrin 0.0 -4.2 ± 8.4* -3.8 ± 7.0* Glucose 0.0 1.7 ± 6.7 2.7 ± 8.0* Inferior vena cava diameter (mm) Icodextrin 0.0 -0.3 ± 7.6 3.5 ± 9.8* Glucose 0.0 -1.7 ± 15.9 -2.7 ± 12.5 LF (0.05-0.15 Hz) Icodextrin 0.0 3.1 ± 17.6 6.1 ± 15.0* Glucose 0.0 -3.0 ± 9.5 -0.7 ± 11.0 HF (0.15-0.40 Hz) Icodextrin 0.0 0.5 ± 17.6 5.2 ± 18.0 Glucose 0.0 -2.9 ± 2.8* -3.9 ± 3.3* NT-pro-BNP (mL) Icodextrin 0.0 -2.5 ± 1.9* -4.2 ± 2.5* Glucose 0.0 -0.9 ± 2.8* -0.9 ± 3.2* TNT (mL) Icodextrin 0.0 -0.9 ± 2.1* -1.2 ± 1.8*

Values are mean ± SD; BP= blood pressure; LVEDD= left ventricular end diastolic diameter; IVD= interventricular septum; LVM= left ventricular mass; LF= power in the low frequency domain; HF= powering the high frequency domain; P values are based on the Student t test, Wilcoxon rank-sum test, or 2 tests according to the variable characteristics. *= p<0.05 vs basal; = p<0.05 vs glucose

ResultsIcodextrin metabolites

182227282824N =

Meses

1296310

Icodext

rin G

2-4

5

4

3

2

1

0

192227282827N =

Meses

1296310

Icodext

rina G

5-7

1.0

.8

.6

.4

.2

0.0

ResultsIcodextrin metabolites

Results Mortality

Group Cause of dropout

Causes of death

Causes of death after dropout

Control (11) Death (6) Hiperkalemia-acidosis (1) Acute myocardial infarct (1) Stroke (1) Peritonitis (2) Sudden death (1) Voluntary (1) Infection [PD] (1) Peritonitis (2) Hiperkalemia-acidosis [HD] (1)*, peritonitis [PD] (1)* Change of address (1) Icodextrin (12) Voluntary (3) Peritonitis [PD] (1), hiperkalemia-acidosis [PD] (1) Peritonitis (1) Peritonitis [PD] (1) * Abdominal pain (1) Sudden death [HD] (1) Peritoneal adherences (1) Hearth failure [HD] (1) Noncompliance (3) Alcoholism (1) Loss of family support (1) Peritonitis [PD] (1) Parkinson (1)

( ) = number of patients. *= Death related to dropout cause. [ ] Dialysis modality at the time of deathDeath was considered related to dropout case if occurred in the 30 days after dropout and the final diagnosis was

related to the technique failure

Results Mortality

0 3 6 9 12 1550

60

70

80

90

100GLU

ICO

log-rank test p<0.01

A

Time

Per

cen

t su

rviv

al

Results Mortality

0 3 6 9 12 1550

60

70

80

90

100GLU

ICO

log-rank test p<0.01

B

Time

Per

cen

t su

rviv

al

Annual Cost of Patient on Dialysis

$-

$50

$100

$150

$200

$250

$300

APD CAPDIcodextrin

CAPD DP HD INST HD SUB

x100

0

Consumables Pharmacologic t Laboratory Hospitalization Peritonitis Catheter dysfunctionDisability Emergency Personal Infrastructure Transport

Results

Relationship of inflammation, ECFv and DM

MALNUTRITIONOR WASTING

MALNUTRITIONOR WASTING

INFLAMMATIONINFLAMMATION CV DISEASECV DISEASE CV DEATHCV DEATH

ECFvEXPANSION

ECFvEXPANSION

PERITONEALPERMEABILITYPERITONEAL

PERMEABILITY PRESSURE VOLUME

PRESSURE VOLUME

D MCHO-PTG

D MCHO-PTG

X X

X X

? ?

xx xx

X X

X X

ICODEXTRINICODEXTRIN

ConclusionConclusion

Patients in the Icodextrin group had better metabolic control and nutrition

Icodextrin-based solution was superior to glucose-based solution in fluid and sodium removal.

Patients in the Icodextrin group had better control of blood pressure and reduction in left ventricular mass

Patients in the Icodextrin group had better metabolic control and nutrition

Icodextrin-based solution was superior to glucose-based solution in fluid and sodium removal.

Patients in the Icodextrin group had better control of blood pressure and reduction in left ventricular mass