What can we expect from enzyme replacement on renal involvement ?

1. L Dubourg Exploration fonctionnelle rénale et Unité de Néphrologie Pédiatrique Hôpital E Herriot et Université Claude Bernard - INSERM U 820 - Lyon What can we expect from enzyme replacement on renal involvement ? ESPN Lyon 2008

2. Fabry disease • X-linked inherited lysosomal storage disorder • deficiency of a-galactosidase A • progressive accumulation of globotriaosylceramide (Gb3)

3. Fabry disease pain gastro-intestinal symptoms early symtoms skin late symtoms kidney heart brain • Accumulation in many types of cells • nervous system • skin • heart • kidney • vascular endothelial cells

4. Renal involvement in Fabry disease Tondel et al., Am J Kidney Disease, 2008

5. Renal involvement in Fabry disease Thurberg et al., kidney int 2002

6. Organ–specific disease progression Breuning et al., J Nephrol, 2008

7. Renal involvement in Fabry disease Branton et al., Medicine, 2002

8. 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 Germain et al., J Am Soc Nephrol 2007

9. ERT Thurberg et al. kidney int 2002 Germain et al., J Am Soc Nephrol 2007

10. ERT Thurberg et al. kidney int 2002 Germain et al., J Am Soc Nephrol 2007

11. ERT Thurberg et al. kidney int 2002 Germain et al., J Am Soc Nephrol 2007

12. ERT Thurberg et al. kidney int 2002 Germain et al., J Am Soc Nephrol 2007

13. Enzyme replacement therapy (ERT) eGFR Germain et al., J Am Soc Nephrol 2007

14. Enzyme replacement therapy (ERT) Germain et al., J Am Soc Nephrol 2007

15. Enzyme replacement therapy alb/creat (mg/mmol) 140 120 100 (n = 6) -0.8 ±0.8 80 inulin clearance (ml/min/1.73 m2) -3.5 ± 1.4 60 (n = 9) 40 20 -4.9 ± 0.9 > 30 0 (n = 10) 2.5 - 30 2 3 4 5 0 1 < 2.5 Time from start of a-Gal treatment (years) • 25 patients • 21 males : 31.1 ± 2.7 years • 4 females : 35.2 ± 8.3 years mean decline in GFR (ml/min/1.73 per year)

16. ERT • double-blind • placebo controlled • median : 18.5 months • 82 patients • mean age  45 years • Pcr 141 ± 44 µmol/l Banikazemi et al., Ann Intern Med, 2007

17. Fabry disease : onset of symptoms Branton et al., Medecine, 2002

18. Fabry disease Tondel et al., Am J Kidney Disease, 2008

19. 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

20. What can we expect from enzyme replacement on renal involvement ? Brenner et al., Curr Opin Nephrol Hypertens, 2004

21. Acknowledgments • Département des Maladies Héréditaires du Métabolisme • Exploration Fonctionnelle rénale et métabolique • Département de Néphrologie Pédiatrique