1. GLYCOGEN STORAGE DISEASE TYPE 1
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

2. Glycogen storage disease type 1 Genetic and molecular bases
Frequency 1: newborns
Autosomal recessive
Two types GSD1a and GSD1b
Genetic and molecular bases
Non metterei ancora alpha in questa dia
Chromosomal loci
GSD1a Glucose-6-phosphatase (G6-Pasea) q21
GSD1b Glucose-6-phosphate Translocase (G6-PT) q23 2

3. Glycogen storage disease type 1 Clinical features
GSD1a/GSD1b
Short stature - delayed puberty
Liver and kidney enlargement
Fasting hypoglycemia
Hyperlipidemia and hyperuricemia
Chronic renal disease
Liver adenoma
Osteoporosis
GSD1b
Neutropenia/Neutrophil dysfunction
Recurrent infections
Inflammatory bowel disease
GSD in parentesi
Types non forms
Glomerulosclerosis IBD o autoimmunity = complications? 3

4. Chronic renal damage: pathogenesis
G6-Pase deficiency in proximal tubular cells (Pan et al., 1998)
Hyperlipidemia
(Yokoyama et al., 1995)
Hyperuricemia
(Mazzali et al., 2001; Kang et al., 2002)
Activation of the angiotensin system (Yiu et al., 2008)

5. Chronic renal damage: histology
Focal glomerulosclerosis
Interstitial fibrosis
Tubular atrophy
(Obara et al., 1993)

6. Chronic renal damage: evolution
Glomerular damage
Hyperfiltration
Microalbuminuria
Proteinuria
Similarity to
Diabetic nephropathy 6

7. Chronic renal damage: therapy
ACE-inhibitors
Anecdotal reports:
Improvement of renal damage
(Baker et al., 1988; Ozen et al., 2000; Pela et al., 2001; Giannì et al., 2002)
Case-control study:
Improvement of glomerular hyperfiltration
No effect on microalbuminuria and proteinuria
(Melis et al., 2005)

8. 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

9. Patients 86 patients 27 on ACE-inhibitors
7 years follow-up of a specific parameter
30 patients
Complete evolution of renal damage

10. Methods and study design
Retrospective-prospective observational study
Biochemical parameters of metabolic control
Glomerular filtration rate, microalbuminuria and proteinuria
Statistical analysis
Mann Whitney and Wilcoxon rank tests
Spearman correlation and chi square tests
Linear regression analysis

11. RESULTS (1): efficacy of ACE-inhibitors on the evolution of each parameter
Glomerular hyperfiltration
Albuminuria
Proteinuria
Treated
Untreated
*p=0.04
n=22
n=20
n=14
n=16
n=12
n=15
years
years
years

12. RESULTS (1): efficacy of ACE-inhibitors on the progression of renal damage
Glomerular hyperfiltration microalbuminuria
n=10
n=20
years 1 2 3 4 5 6
Microalbuminuria proteinuria
n=10
n=20
years 1 2 3 4 5 6
Treated
Untreated

13. RESULTS (2): role of the metabolic control
*p=0.01
Treated patients
Albumin/creatinine ratio
*p=0.003
Mild
Proteinuria mg/24h
Severe
Triglyceridemia (mg/dl)
Mild
Severe
Cholesterolemia (mg/dl)

14. RESULTS (2): role of the metabolic control
Untreated patients
*p=0.04
Albumin/creatinine ratio
*p=0.004
Proteinuria mg/24h
Mild
Severe
Triglyceridemia (mg/dl)
Mild
Severe
Cholesterolemia (mg/dl)

15. RESULTS (3a): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Glomerular hyperfiltration
Treated
Untreated
Glomerular filtration rate ml/min/1.73
*p=0.02
Severe hyperlipidemia
n=12
n=8
Mild hyperlipidemia
n=14
n=8

16. RESULTS (3b): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Microalbuminuria
albumin/creatinine mg/mmol ratio
*p=0.04
Treated
Untreated
Severe hyperlipidemia
n=9
n=5
Mild hyperlipidemia
n=9
n=7
Hypertriglyceridemia predictive factor of ACE-inh inefficacy (p=0.03).

17. RESULTS (3c): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Proteinuria
Proteinuria mg/24h
*p=0.001
Treated
Untreated
n=8
Severe hyperlipidemia
n=5
Mild hyperlipidemia
n=7
n=7
Hypercholesterolemia predictive factor of ACE-inh inefficacy (p=0.02).

18. Glomerular hyperfiltration microalbuminuria
RESULTS (3d): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Glomerular hyperfiltration microalbuminuria
Severe hyperlipidemia
Mild hyperlipidemia
n=4
n=13
years 1 2 3 4 5 6
*p=0.04
n=6
n=7
years 1 2 3 4 5 6 7 8
Hypertriglyceridemia predictive factor of ACE-inh inefficacy (p=0.04).
Treated
Untreated

19. Microalbuminuria proteinuria
RESULTS (3e): interference of the altered metabolic environment on the efficacy of the ACE-inhibitors
Microalbuminuria proteinuria
Severe hyperlipidemia
Mild hyperlipidemia
n=4
n=13
years 1 2 3 4 5 6
*p=0.006
n=6
n=7
years 1 2 3 4 5 6 7 8
Treated
Untreated

20. CONCLUSIONS Suggestions
ACE-inhibitors improve and delay the progression of renal damage in GSD1 patients with mild hyperlipidemia
Suggestions
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

21. Italian study group on GSD1
Naples
G. Andria
R. Della Casa
D. Melis
G. Parenti
Monza
Siena
R. Parini
M. Rigoldi
A. Benedetti
P. Marcolongo
Milan
M. Giovannini
S. Paci
Genoa
Rome
M. Di Rocco
C. Dionisi Vici
F. Deodato
Padoa
Burlina
L. Giordano
Palermo
L. Iapichino
M. Caserta
C. Castana
Bari
Florence
F. Papadia
A. Donati

23. Hypotheses Activation of NADPH oxidase
Lipids
Uric Acid
Glucose 6P
Activation of NADPH oxidase
Increased angiotensinogen expression
Increased expression of angiotensin receptor 1
TGF-b1
Increased expression of TGF-b1
Han Yiu et al., 2008 23

24. Ceriello A, 2006

25. Evcimen ND, King GL, 2007

26. Evcimen ND, King GL, 2007

27. Kardon et al., 2008

28. Ceriello A, 2006

29. El Nahas A, Bello A, 2005

30. El Nahas A, Bello A, 2005

32. RESULTS (3): interference of the altered metabolic enviroment on the efficacy of the ACE-inhibitors
Patients with mild hyperlipidemia
*p=0.02
Therapy
Non therapy

33. Results (4): interference of the altered metabolic enviroment on the efficacy of the ACE-inhibitors
Patients with mild hyperlipidemia
*p=0.04
Therapy
Non therapy

34. RESULTS (5): interference of the altered metabolic enviroment on the efficacy of the ACE-inhibitors
Patients with mild hyperlipidemia
*p=0.001
Therapy
Non therapy