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Hyperlipidemia affects the efficacy of the ACE- inhibitors: an Italian multicenter study on GLYCOGEN STORAGE DISEASE TYPE 1 Daniela Melis Department of.

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Presentation on theme: "Hyperlipidemia affects the efficacy of the ACE- inhibitors: an Italian multicenter study on GLYCOGEN STORAGE DISEASE TYPE 1 Daniela Melis Department of."— Presentation transcript:

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 2 nd 2010

2 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: newborns Autosomal recessive Two types GSD1a and GSD1b

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

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

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

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

7 ACE-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

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 52 patients 7 years follow-up of a specific parameter 30 patients Complete evolution of renal damage 27 on ACE-inhibitors

10 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

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

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

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

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

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

16 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 albumin/creatinine mg/mmol ratio *p=0.04 Treated Untreated n=9 n=5 n=9 n=7

17 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). Proteinuria mg/24h *p=0.001 Treated Untreated Proteinuria n=8 n=5 n=7

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

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

20 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

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

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

24 Ceriello A, 2006

25 Evcimen ND, King GL, 2007

26

27 Kardon et al., 2008

28 Ceriello A, 2006

29 El Nahas A, Bello A, 2005

30

31

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

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

34 Therapy Non 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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