Hyperlipidemia affects the efficacy of the ACE-
inhibitors: an Italian multicenter study on
GLYCOGEN STORAGE DISEASE TYPE 1
Daniela Melis Department of Pediatrics, “Federico II” University
Naples, Italy
International Meeting Glycogen Storage Diseases Associations, Milan October 2nd 2010
Glycogen storage disease type 1
Genetic and molecular bases
Chromosomal loci
GSD1a Glucose-6-phosphatase (G6-Pase 17q21 GSD1b Glucose-6-phosphate Translocase (G6-PT) 11q23
Frequency 1:100.000 newborns
Autosomal recessive
Two types GSD1a and GSD1b
Glycogen storage disease type 1 Clinical features
GSD1a/GSD1b
Short stature - delayed pubertyLiver and kidney enlargementFasting hypoglycemiaHyperlipidemia and hyperuricemia
Chronic renal diseaseChronic renal diseaseLiver adenomaOsteoporosis
GSD1b
Neutropenia/Neutrophil dysfunctionRecurrent infections
Inflammatory bowel disease
Chronic renal damage: pathogenesis
HyperlipidemiaHyperlipidemia (Yokoyama et al., 1995)
Activation of the angiotensin systemActivation of the angiotensin system (Yiu et al., 2008)
G6-Pase deficiency in proximal tubular cellsG6-Pase deficiency in proximal tubular cells (Pan et al., 1998)
HyperuricemiaHyperuricemia (Mazzali et al., 2001; Kang et al., 2002)
Chronic renal damage: histology
Focal glomerulosclerosis Focal glomerulosclerosis Interstitial fibrosisInterstitial fibrosis Tubular atrophy Tubular atrophy
(Obara et al., 1993)
Chronic renal damage: evolution
Glomerular damageGlomerular damage HyperfiltrationHyperfiltration
Microalbuminuria Microalbuminuria ProteinuriaProteinuria
Similarity toSimilarity toDiabeticDiabetic nephropathy nephropathy
ACE-inhibitorsACE-inhibitors
Case-control study: Improvement of glomerular hyperfiltration No effect on microalbuminuria and proteinuria
(Melis et al., 2005)
Anecdotal reports: Improvement of renal damage
(Baker et al., 1988; Ozen et al., 2000; Pela et al., 2001; Giannì et al., 2002)
Chronic renal damage: therapy
Aim of the study
1- To evaluate the efficacy of ACE-inhibitors on renal damage of GSD1 patients
2- To investigate the role of the metabolic control on the initiation and progression of GSD1-related nephropathy
3- To analyze the interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Patients
86 patients
52 patients
7 years follow-up of a specific parameter
30 patients
Complete evolution of renal damage
27 on ACE-inhibitors
Methods and study design
Statistical analysis
Mann Whitney and Wilcoxon rank tests
Spearman correlation and chi square tests
Linear regression analysis
Glomerular filtration rate, microalbuminuria and proteinuria
Biochemical parameters of metabolic control
Retrospective-prospective observational study
RESULTS (1): efficacy of ACE-inhibitors on the evolution of each parameter
0 1 2 3 4 5 6 7 8100
150
200
250
Glo
me
rula
r fi
ltra
tio
n r
ate
ml/
min
/1.7
3 m
q
Glomerular hyperfiltration
0 1 2 3 4 5 6 7 80
5
10
15
20
25
alb
um
in/c
reat
inin
e ra
tio
mg
/mm
ol
Albuminuria0 1 2 3 4 5 6 7 8
0
400
800
1200
pro
tein
uri
a m
g/2
4h
Proteinuria
TreatedUntreated
*p=0.04
n=22
n=20
n=14
n=16
n=12
n=15
years
years
years
RESULTS (1): efficacy of ACE-inhibitors on the progression of renal damage
TreatedUntreated
Glomerular hyperfiltration microalbuminuria
n=10
n=20
years1 2 3 4 5 6
Microalbuminuria proteinuria
n=10
n=20
years1 2 3 4 5 6
RESULTS (2): role of the metabolic control
Alb
um
in/c
reat
inin
e ra
tio
Triglyceridemia (mg/dl)
Pro
tein
uri
a m
g/2
4h
Cholesterolemia (mg/dl)
*p=0.01
*p=0.003
Treated patients
Mild Severe
Mild Severe
RESULTS (2): role of the metabolic control
Alb
um
in/c
reat
inin
e ra
tio
Triglyceridemia (mg/dl)
Pro
tein
uri
a m
g/2
4h
Cholesterolemia (mg/dl)
*p=0.04
*p=0.004
Untreated patients
Mild Severe
Mild Severe
Severe hyperlipidemia
RESULTS (3a): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Mild hyperlipidemia
0 1 2 3 4 5 6 7 8100
150
200
250
300
350
years
0 1 2 3 4 5 6 7 8100
150
200
250
years
TreatedUntreated
Glo
mer
ular
filtr
atio
n ra
te m
l/min
/1.7
3
*p=0.02
Glomerular hyperfiltration
n=12
n=8
n=8
n=14
RESULTS (3b): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Hypertriglyceridemia predictive factor of ACE-inh inefficacy (p=0.03).
Severe hyperlipidemia
Mild hyperlipidemia
Microalbuminuria
0 1 2 3 4 5 60
2
4
6
8
10
years
0 1 2 3 4 5 60
10
20
30
40
years
albu
min
/cre
atin
ine
mg/
mm
ol r
atio
*p=0.04
TreatedUntreated
n=9
n=5
n=9
n=7
RESULTS (3c): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Severe hyperlipidemia
Mild hyperlipidemia
Hypercholesterolemia predictive factor of ACE-inh inefficacy (p=0.02).
0 1 2 3 4 5 60
500
1000
1500
years
0 1 2 3 4 5 60
500
1000
years
Pro
tein
uria
mg/
24h
*p=0.001
TreatedUntreated
Proteinuria
n=8
n=5
n=7
n=7
Glomerular hyperfiltration microalbuminuria
Severe hyperlipidemia Mild hyperlipidemia
RESULTS (3d): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
TreatedUntreated
Hypertriglyceridemia predictive factor of ACE-inh inefficacy (p=0.04).
n=4
n=13
years1 2 3 4 5 6
*p=0.04n=6
n=7
years
1 2 3 4 5 6 7 8
RESULTS (3e): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
TreatedUntreated
Microalbuminuria proteinuria
Severe hyperlipidemia Mild hyperlipidemia
n=4
n=13
years1 2 3 4 5 6
*p=0.006n=6
n=7
years
1 2 3 4 5 6 7 8
CONCLUSIONS
ACE-inhibitors improve and delay the progression of renal damage in GSD1 patients with mild hyperlipidemia
Importance of a strict follow-up of chronic kidney disease
Need for a precocious start of ACE-inhibitors treatment
Possible effect of a lipid reduction treatment
Suggestions
Italian study group on GSD1
G. AndriaR. Della CasaD. MelisG. Parenti
A. BenedettiP. Marcolongo
R. PariniM. Rigoldi
M. GiovanniniS. Paci
C. Dionisi ViciF. Deodato
L. IapichinoM. CasertaC. Castana
A. BurlinaB. L. Giordano
Naples
Monza
Milan
Padoa
Rome
Palermo
Siena
Genoa
FlorenceBari
M. Di Rocco
F. Papadia A. Donati
Hypotheses
Han Yiu et al., 2008
TGF-TGF-11
LipidsUric AcidGlucose 6P
Increased expression of angiotensin receptor 1
Increased angiotensinogen expression
Increased expression of TGF-1
Activation of NADPH oxidase
Ceriello A, 2006
Evcimen ND, King GL, 2007
Evcimen ND, King GL, 2007
Kardon et al., 2008
Ceriello A, 2006
El Nahas A, Bello A, 2005
El Nahas A, Bello A, 2005
0 1 2 3 4 5 6 7 8110
210
Glo
me
rula
r fi
ltra
tio
n r
ate
ml/
min
/1.7
3
years
TherapyNon therapy
RESULTS (3): interference of the altered metabolic enviroment on the efficacy of the ACE-inhibitors
Patients with mild hyperlipidemia
*p=0.02
0 1 2 3 4 5 60
2
4
6
8
10
alb
um
in/c
reat
inin
e m
g/m
mo
lra
tio
years
TherapyNon therapy
Results (4): interference of the altered metabolic enviroment on the efficacy of the ACE-inhibitors
Patients with mild hyperlipidemia
*p=0.04
0 1 2 3 4 5 60
250
500
750
1000
1250
years
pro
tein
uri
a m
g/2
4h
TherapyNon therapy
RESULTS (5): interference of the altered metabolic enviroment on the efficacy of the ACE-inhibitors
Patients with mild hyperlipidemia
*p=0.001
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