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