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

Glycogen storage disease type 1 Genetic and molecular bases Frequency 1:100.000 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) 17q21 GSD1b Glucose-6-phosphate Translocase (G6-PT) 11q23 2

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

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)

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

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

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)

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

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

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

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

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)

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)

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

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).

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).

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

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

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

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

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

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

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

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

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