Impacto metabólico e estratégias para redução do risco cardiovascular em DP

Roberto Pecoits-Filho

Potential conflict of interest

• Honoraria– Gambro, Altana, Baxter, Renal Research Institute, Roche,

University of Missouri, Genzyme • Research Grants

– CNPq, Fundação Araucária, Fundação Pro Renal, Baxter, Astra Zeneca, Amgen, Biogenerix, Genzyme

• Consulting– Crescendo Medical Education (www.thekidney.org), Baxter,

Roche, Genzyme

Kramer HJ et al J Am Soc Nephrol 2006; 17:1453-9

Chan J, et al Nephrology Dialysis Transplantation 2007; 22(4):1100-1106

Bone remodeling

Acute phase reactants

Partialy corrected uremia

Muscle catabolism

Endothelial dysfunction Monocyte adhesion SMC proliferation LDL oxidation appetite

REE

adipocytokine production

Increased innate immune responseDeffective adaptive immune response

Insulin resistyanceMetabolic syndrome

• Lameire et al – 5 casos de de novo diabetes mellitus em 310 pacientes não

diabéticos entre 1979 and 1996

• Outras séries– de novo diabetes em 5% de pacientes

Lameire N, et al. Clin Nephrol 1988; 30 (Suppl 1): S53-58.Kurtz SB, et al. Mayo Clin Proc 1983; 58: 633-639.

Hiperglicemia pós PDHiperglicemia pós PD

• Glicemia de jejum (fasting after overnight dwell with 1.5% glucose)

• 153 DM / 252 non-DM patients

• Fasting plasma glucose – 126 - 200 mg/dL - 48 patients (19.0%) – >200mg/dl – 11 patients (4.4%)

New Onset Hyperglycemia in Non-Diabetic Chinese Patients New Onset Hyperglycemia in Non-Diabetic Chinese Patients Started on Peritoneal DialysisStarted on Peritoneal Dialysis

Szeto CC. Am J Kidney Dis 2007 Apr;49(4):524-32.

Gordura corporal em PD

Fernstrom at al PDI, Vol 18, pp. 166-171, 1998

Peso KG 67.1 68.4 ns

% Gordura 27.8 30.9 ns

Gordura abdominal (cm2) 130.1 159.7 P<0.02

Dexa CT scans, 12 pacientes incidentes

Disturbances of carbohydrate metabolism in non-diabetic PD patients

PD HD p value Fasting glucose (mg/dL) 90±16 81±14 <0.005

1 (%)HbA C 6.1±0.8 5.4±0.5 <0.0001 1 > 7%HbA c (%) 6 0 <0.005

HOMA index 3.3±3.2 2.1±2.0 <0.05 Fibrinogen ( /mg dL) 582±183 452±183 <0.001

Fortes et al. ISPD Hong Kong 2006

Metabolic Syndrome and Dialysis

Fortes et al. ASN 2006

%

Davies et al, KI, 1998 and Peritoneal Davies et al, KI, 1998 and Peritoneal Biopsy RegistryBiopsy Registry®®

00..66

00..6655

00..77

00..7755

11 66 1122 1188 2244 3300 3366 4422 4488 5544 6600

MMoonntthhss oonn PPeerriittoonneeaall DDiiaallyyssiiss

So

lute

Tra

nsp

ort

(D

/P c

reat

)

Changes in membrane structure and Changes in membrane structure and function with time on PDfunction with time on PD

Increased vascular area in experimental diabetes

De Vriese et al. JASN 2001; 12 1734-41

Problemas metabólicos aumentam nos alto transportadores

Reabsorção de glicose Obesidade

Dislipidemia

Resistência insulínica

Aumento da perda proteica Hipoalbuminemia

Perda da capacidade antioxidante

Edema

Falha de UF Sobrecarga de volume

Inflamação

Aumento de mortalidade

ADEMEX : Diabetes Mellitus

p=0.3237

p=0.7203

Months on Study

% P

atie

nt S

urv

ival

follow up (months)

0 6 12 18 24 30 36

act

uari

al s

urv

iva

l

0.5

0.6

0.7

0.8

0.9

1.0

pre-existing diabetes

FBS < 100 mg/dL

FBS 100 to 126 mg/dL

univariate Cox regression, p = 0.020

FBS > 126 mg/dL

Fasting blood glucose predicts survival in PD patientsFasting blood glucose predicts survival in PD patients

Szeto CC. Am J Kidney Dis 2007 Apr;49(4):524-32.

Abbott KG et alKidney Int 2004; 65:597-605

BMI≥30

BMI<30

BMI≥30

BMI<30

HD PD

Obesidade reduz a sobrevida de pacientes Obesidade reduz a sobrevida de pacientes em PDem PD

McDonald SP et al J Am Soc Nephrol 2003; 14: 2894-901

N=9769Obesity HR 1.35

<20

20-24.9

25-29.9>30

P<0.001

Diferenças da relação entre mortalidade Diferenças da relação entre mortalidade e obesidade: PD e HDe obesidade: PD e HD

• Em diálise peritoneal– a obesidade está relacionada a risco de

complicações de cateter e infecções– Mais frequentemente relacionada a acúmulo de

gordura no abdomen– Mais frequentemente associada a distúrbios

metabólicos

Morioka et al: Diabetes Care 24: 909-913, 2001

P = 0.005

Wu et al: NDT 12: 2105-10, 1997

Programas de redução de peso em PDProgramas de redução de peso em PD

• 11 pacientes com mais de 25 de IMC• Equipe multidisciplinar

– Refeições planejadas – Programa de exercícios– Otimização de prescrição

Hollis J et al Perit Dial Int 25(Suppl 3): S152-4, 2005

Weight reduction program in PDWeight reduction program in PD

Hollis J et al Perit Dial Int 25(Suppl 3): S152-4, 2005

N=8 0 mo 12 mo P value

Weight (kg) 94.6 89.5 0.017

Energy intake (kcal/d)

1824 1208 0.012

PD energy (kcal/d) 350 339 NS

PD volume (L/d) 8.75 10.75 NS

Kt/V 2.26 2.28 NS

% Body fat 41.2 40.2 NS

Volume 17, 2001

Adapted from Johnson DW et al Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload BMC Nephrology 2001,2 :2

8.97.9

5

5.5

6

6.5

7

7.5

8

8.5

9

9.5

HbA

1c %

Glucose Icodextrin

* P <0.05

Substitution of one glucose exchange with icodextrin results in a significant fall in HbA1c

Prospective, open label study of 17 PD patients with symptomatic fluid overload

A subset of 12 insulin treated diabetic APD and CAPD patients

Substitution of one 4.25% for Extraneal. All other exchanges remained the same

*

Baseline 1 month post Icodextrin

ResultsInsulin dose

0 3 6 9 12

-15

-10

-5

0

5

10GLU

ICO

* p<0.05 ICO vs GLU+p<0.01 ICO vs GLU

+++

++++**

*

Months

In

sulin

dos

e (U

/d)

ResultsBlood glucose

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

-100

-75

-50

-25

0

25

50

75

100GLU

ICO

* p<0.05 ICO vs GLU

**

Months

F

asti

ng s

erum

Glu

cose

(m

g/dL

)

ResultsGlycated hemoglobin

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

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0GLU

ICO

* p<0.05 ICO vs GLU+p<0.01 ICO vs GLU

* *

+

+

Months

H

b a1

c (%

)

ResultsTriglycerides

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

-200

-150

-100

-50

0

50

100GLU

ICO

* p<0.05 ICO vs GLU+p<0.01 ICO vs GLU

+

+

Months

S

erum

Tri

glyc

erid

es(m

g/dL

)

ResultsSurvival

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 1550

60

70

80

90

100GLU

ICO

log-rank test p<0.01

Time

Per

cent

sur

viva

l

NEPP

DDDD

PPPP

Marshall J et al. Kidney Int 2003; 64: 1480-1486

4D Study4D Study

Wanner C et al N Engl J Med 2005; 353(3):238-48

Fellstrom B et al. N Engl J Med 2009;10.1056/NEJMoa0810177

AURORA

Paciente DRC/ HD / DP

•Colesterol Total•TG

•HDL, LDL

Perfil patológico•TG>180mg%•LDL>100mg%•HDL<40mg%

Sem perfil patológico

Cada 6 meses:•Colesterol•TG•HDL, LDL

Hiperlipidemia combinadaestatinas

Metat: LDL<1oomg%

HipertligiceridemiaGemfibrozil

Meta:: TG<180mg%

Não combine!!

Cada 6 meses:•Colesterol•TG•HDL, LDL•Enzimas hepaticas

NDT 2000: Vol 15, Suppl. 5

Martens FM, et al. Drugs 2002; 62: 1463-1480.

52 DM with Stable glycemic control on insulin on PD

Insulin + Add on RSZ 4mg daily

Insulin alone

Randomized24 wks

Wong et al. Am J Kidney Dis 2005 Oct;46(4):713-9

Improve Insulin Resistance Percentage reduction in insulin dosage was markedly more

significant in RSZ group than control group [-21% vs -0.5%]

Wong TY, …, Li PKT. Am J Kidney Dis 2005 Oct;46(4):713-9

Change in hsCRPse

rum

CR

P (

mg

/L)

0

2

4

6

8

10

12

14

0 week 24 week

TZD CTL TZD CTL

p = 0.03p = 0.01

Wong TY, …, Li PKT. Am J Kidney Dis 2005 Oct;46(4):713-9

Longitudinal Assessment of Numerous Discrete

Modifications of Atherosclerotic Risk factors in Kidney disease

LANDMARKLANDMARK

Isbel NM et al Am Heart J 2006; 151(3):745-53

(N=200)(49 PD, 78 HD, 73 pre-dialysis)

LANDMARK TrialLANDMARK TrialParameter Usual Care Focused Care Visits 2 Monthly Monthly Smoking Usual Psych, QUIT Lipids TC<5.5,

LDL<3 TC<4, LDL<2,

TG<2 Hcy No Target Hcy<15 BP 160/90 <140/90 Hb 10-12.5 11-12.5 Pi <1.8 <1.6 PTH 2-3 x N 2-3 x N HbA1C No Target <8% Aspirin Clinical Indicn All Patients

Isbel NM et al Am Heart J 2006; 151(3):745-53

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive

Sur

viva

l

0 5 10 15 20 25Survival (months of follow up)

randomis = 1 randomis = 2

Event free survival by randomization group

Isbel NM et al Am Heart J 2006; 151(3):745-53

Usual Care Vs Focus Care

HD vs. PD in DMUSRDS Mortality 1987-2005

First year

Third year

Second Year

Courtesy Dr. Heaf

Conclusões

• Alterações do metabolismo de glicose e lípides são comuns em DRC

• Absorção de glicose piora os distúrbios em DP, particularmente em alto transportadores

• Intervenções são eficazes • Redução na mortalidade ainda precisa ser demonstrada