ESPN Lyon 2008

What can we expect from enzyme

replacement on renal involvement ?

L Dubourg

Exploration fonctionnelle rénale et Unité de Néphrologie Pédiatrique

Hôpital E Herriot et Université Claude Bernard - INSERM U 820 - Lyon

Fabry disease

X-linked inherited lysosomal storage disorder

deficiency of -galactosidase A

progressive accumulation of

globotriaosylceramide (Gb3)

Fabry disease

Accumulation in many types of cells

nervous system skin heart kidney vascular endothelial

cells

gastro-intestinal symptom

s

pain

skin

early symtoms

brainheartkidney

late symtoms

Renal involvement in Fabry disease

Tondel et al., Am J Kidney Disease, 2008

Renal involvement in Fabry disease

Thurberg et al., kidney int 2002

Organ–specific disease progression

Breuning et al., J Nephrol, 2008

Renal involvement in Fabry disease

Branton et al., Medicine, 2002

Germain et al., J Am Soc Nephrol 2007

Enzyme replacement therapy (ERT)

double-blind placebo controlled period 54 months 58 patients (56 males) mean age 31.1 years Pcr 71 ± 17.7 µmol/l

Thurberg et al. kidney int 2002

Germain et al., J Am Soc Nephrol 2007

ERT

Thurberg et al. kidney int 2002

Germain et al., J Am Soc Nephrol 2007

ERT

Thurberg et al. kidney int 2002

Germain et al., J Am Soc Nephrol 2007

ERT

Thurberg et al. kidney int 2002

Germain et al., J Am Soc Nephrol 2007

ERT

Enzyme replacement therapy (ERT)

eGFR

Germain et al., J Am Soc Nephrol 2007

Enzyme replacement therapy (ERT)

Germain et al., J Am Soc Nephrol 2007

Enzyme replacement therapy

25 patients 21 males : 31.1 ± 2.7 years 4 females : 35.2 ± 8.3 years

0

20

40

60

80

100

120

140

31 2 40 5

Time from start of -Gal treatment (years)

inul

in c

lear

ance

(m

l/min

/1.7

3 m

2 )

< 2.52.5 - 30> 30

alb/creat (mg/mmol)

(n = 6)

(n = 9)

(n = 10)

mean decline in GFR

(ml/min/1.73 per year)

-0.8 ±0.8 -3.5 ± 1.4

-4.9 ± 0.9

ERT

Banikazemi et al., Ann Intern Med, 2007

double-blind placebo controlled median : 18.5 months 82 patients mean age 45 years Pcr 141 ± 44 µmol/l

Branton et al., Medecine, 2002

Fabry disease : onset of symptoms

Fabry disease

Tondel et al., Am J Kidney Disease, 2008

ERT in children

Ries et al., Pediatrics, 2006 Ramaswami et al., Acta Paediatrica, 2007 Wraith et al., J Pediatr, 2008

results

safety

normalisation of Gb3 plasma concentration

decrease in pain and gastro-intestinal symptoms

improvement of autonomic function

decrease in micro-albuminuria

Brenner et al., Curr Opin Nephrol Hypertens, 2004

What can we expect from enzyme replacement on renal involvement ?

Acknowledgments

Département des Maladies Héréditaires du

Métabolisme

Exploration Fonctionnelle rénale et métabolique

Département de Néphrologie Pédiatrique