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
Increased innate immune response
Deffective adaptive immune response
Partialy corrected uremia
 Bone remodeling
Insulin resistyance
Metabolic syndrome
 Muscle catabolism
 Acute phase reactants
 adipocytokine production
 appetite
 REE
 Endothelial dysfunction
 Monocyte adhesion
 SMC proliferation
 LDL oxidation
Hiperglicemia pós PD
• 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.
New Onset Hyperglycemia in Non-Diabetic Chinese Patients
Started on Peritoneal Dialysis
• 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%)
Szeto CC. Am J Kidney Dis 2007 Apr;49(4):524-32.
Gordura corporal em PD
Dexa CT scans, 12 pacientes incidentes
Peso KG
67.1
68.4
ns
% Gordura
27.8
30.9
ns
Gordura abdominal
(cm2)
130.1
159.7
P<0.02
Fernstrom at al PDI, Vol 18, pp. 166-171, 1998
Disturbances of carbohydrate metabolism
in non-diabetic PD patients
Fasting glucose (mg/dL)
HbA1C (%)
HbA1c > 7% (%)
HOMA in dex
Fibrinogen (mg/d L)
PD
9016
6.10.8
6
3.33.2
582183
HD
8114
5.40.5
0
2.12.0
452183
p value
<0.005
<0.0001
<0.005
<0.05
<0.001
Fortes et al. ISPD Hong Kong 2006
Metabolic Syndrome and Dialysis
%
Fortes et al. ASN 2006
Changes in membrane structure and
function with time on PD
Solute Transport (D/P creat)
0.75
0.7
0.65
0.6
1
6
12
18
24
30
36
42
48
54
60
Months on Peritoneal Dialysis
Davies et al, KI, 1998 and Peritoneal Biopsy Registry®
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
% Patient Survival
ADEMEX : Diabetes Mellitus
p=0.3237
p=0.7203
Months on Study
Fasting blood glucose predicts survival in PD patients
1.0
FBS < 100 mg/dL
0.9
actuarial survival
FBS 100 to 126 mg/dL
FBS > 126 mg/dL
0.8
0.7
pre-existing diabetes
0.6
univariate Cox regression, p = 0.020
0.5
0
6
12
18
24
30
36
follow up (months)
Szeto CC. Am J Kidney Dis 2007 Apr;49(4):524-32.
PD
HD
BMI≥30
BMI≥30
BMI<30
BMI<30
Abbott KG et alKidney Int 2004; 65:597-605
Obesidade reduz a sobrevida de pacientes em PD
P<0.001
<20
N=9769
Obesity HR 1.35
20-24.9
>30
25-29.9
McDonald SP et al J Am Soc Nephrol 2003; 14: 2894-901
Diferenças da relação entre mortalidade
e 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
P = 0.005
Morioka et al: Diabetes Care 24: 909-913, 2001
Wu et al: NDT 12: 2105-10, 1997
Programas 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 PD
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
Hollis J et al Perit Dial Int 25(Suppl 3): S152-4, 2005
Volume 17, 2001
Substitution of one glucose exchange with icodextrin results in a
significant fall in HbA1c
HbA1c %
* P <0.05
9.5
9
8.5
8
7.5
7
6.5
6
5.5
5
*
 Prospective, open label
study of 17 PD patients with
symptomatic fluid overload
 A subset of 12 insulin
treated diabetic APD and
CAPD patients
8.9
7.9
Baseline
Glucose
 Substitution of one 4.25%
for Extraneal. All other
exchanges remained the
same
1 month post
Icodextrin
Icodextrin
Adapted from Johnson DW et al Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload BMC
Nephrology 2001,2 :2
Results
Insulin dose
 Insulin dose (U/d)
10
GLU
ICO
5
* p<0.05 ICO vs GLU
+p<0.01 ICO vs GLU
0
-5
*
*
-10
*
+
+ +
+
+
+
+
-15
0
3
6
Months
9
12
Results
Blood glucose
 Fasting serum
Glucose (mg/dL)
100
GLU
75
ICO
50
* p<0.05 ICO vs GLU
25
0
-25
*
-50
*
-75
-100
0
3
6
Months
Mean±EEM
*p<0.05; ** p<0.03; *** p<0.01 vs Control
‡p<0.05; ‡ ‡ p<0.03; ‡ ‡ ‡ p<0.01 vs Basal
9
12
Results
 Hb a1c (%)
Glycated hemoglobin
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
GLU
ICO
* p<0.05 ICO vs GLU
+p<0.01 ICO vs GLU
*
+
0
3
6
Months
Mean±EEM
*p<0.05; ** p<0.03; *** p<0.01 vs Control
‡p<0.05; ‡ ‡ p<0.03; ‡ ‡ ‡ p<0.01 vs Basal
+
*
9
12
Results
 Serum Triglycerides
(mg/dL)
Triglycerides
100
GLU
50
ICO
0
* p<0.05 ICO vs GLU
+p<0.01 ICO vs GLU
-50
+
-100
+
-150
-200
0
3
6
Months
Mean±EEM
*p<0.05; ** p<0.03; *** p<0.01 vs Control
‡p<0.05; ‡ ‡ p<0.03; ‡ ‡ ‡ p<0.01 vs Basal
9
12
Results
Survival
100
Percent survival
GLU
ICO
90
80
70
60
log-rank test p<0.01
50
0
3
6
9
Time
Mean±EEM
*p<0.05; ** p<0.03; *** p<0.01 vs Control
‡p<0.05; ‡ ‡ p<0.03; ‡ ‡ ‡ p<0.01 vs Basal
12
15
PPPP
DDDD
NEPP
Marshall J et al. Kidney Int 2003; 64: 1480-1486
4D Study
Wanner C et al N Engl J Med 2005; 353(3):238-48
AURORA
Fellstrom B et al. N Engl J Med 2009;10.1056/NEJMoa0810177
Paciente DRC/ HD / DP
Cada 6 meses:
•Colesterol
•TG
•HDL, LDL
Cada 6 meses:
•Colesterol Total
•TG
•HDL, LDL
Sem perfil patológico
•Colesterol
•TG
•HDL, LDL
•Enzimas hepaticas
Perfil patológico
•TG>180mg%
•LDL>100mg%
•HDL<40mg%
Hiperlipidemia combinada
estatinas
Metat: LDL<1oomg%
Não combine!!
Hipertligiceridemia
Gemfibrozil
Meta:: TG<180mg%
NDT 2000: Vol 15, Suppl. 5
Martens FM, et al. Drugs 2002; 62: 1463-1480.
24 wks
Randomized
52 DM with Stable glycemic
control on insulin on PD
Insulin + Add on
RSZ 4mg daily
Insulin alone
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 hsCRP
14
p = 0.01
p = 0.03
serum CRP (mg/L)
12
10
8
6
4
2
0
TZD
CTL
0 week
TZD
CTL
24 week
Wong TY, …, Li PKT. Am J Kidney Dis 2005 Oct;46(4):713-9
LANDMARK
Longitudinal Assessment of
Numerous Discrete
Modifications of Atherosclerotic
Risk factors in Kidney disease
(N=200)
(49 PD, 78 HD, 73 pre-dialysis)
Isbel NM et al Am Heart J 2006; 151(3):745-53
LANDMARK Trial
Parameter Usual Care Focused Care
Visits
2 Monthly
Monthly
Smoking
Usual
Psych, QUIT
Lipids
TC<5.5,
TC<4, LDL<2,
LDL<3
TG<2
Hcy
No Target
Hcy<15
BP
<140/90
160/90
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
1.00
v e
n
t
f r e
e
s
u
r v i v a
l
b
y
r a
n
d
o
m
i z a
t i o
n
g
r o
u
p
0.50
0.75
E
0.00
0.25
Usual Care Vs Focus Care
0
5
10
15
Survival (months of follow up)
randomis = 1
20
25
randomis = 2
Isbel NM et al Am Heart J 2006; 151(3):745-53
HD vs. PD in DM
USRDS Mortality 1987-2005
Second Year
First year
Third 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