1. Diagnosis and Treatment of Renal manifestations in GSD I G.P.A. Smit Beatrix Children’s Hospital UMC Groningen NL

2. GSD I Renal manifestations Introduction Natural course Renopreservation Pregnancy Pathophysiology Conclusions

3. GSD I Renal manifestations Introduction

4. GSD I Short stature Hepatomegaly Nephromegaly Hypoglycemia Lactic acidemia Hyperuricemia Hyperlipidemia

5. J.Y.Chou et al 2007

9. GSD I Introduction Large kidneys Hyperfiltration Glomerulosclerosis Proteinuria Renal failure Tubular dysfunction Renal stones

10. GSD I Introduction GSD I nephropathy: Large kidneys Hyperperfusion Hyperfiltration Intraglomerular P ++ Glomerulosclerosis Proteinuria Renal failure No Hypertension (7%) Diabetic nephropathy: Normal Hyperperfusion Hyperfiltration Intraglomerular P ++ Glomerulosclerosis Proteinuria Renal failure Hypertension

11. Progressive thickening of the glomerular basement membrane Increase of the extracelluar matrix Wolf G. et al EJCI 2004

12. Focal Segmental Glomerulosclerosis

13. Progressive thickening of the glomerular basement membrane Increase of the extracelluar matrix GSD I Glycogen deposition Wolf G. et al EJCI 2004

14. GSD I Renal manifestations Introduction Natural course

15. ESGSD European Study on Glycogen Storage Disease type I * aims: -to study clinical course, treatment, outcome -to study pathophysiology (complications) -to share experience and knowledge - to develop new therapeutic strategies *main goal: -to reach consensus about long-term management and follow-up Rake JP Visser G 2002

16. Participants ESGSD Austria W Endres, D Skladal, Innsbruck Belgium E Sokal, Brussels Czech Republic J Zeman, Praque France Ph Labrune, Clamart Germany P Bührdel, Leipzig K Ullrich, Münster (Hamburg) G Däublin, U Wendel, Düsseldorf Great Britain P Lee, JV Leonard, G Mieli-Vergani, London Hungary L Szönyi, Budapest Italy P Gandullia, R Gatti, M di Rocco,Genova D Melis, G Andria, Napoli Israel S Moses, Beersheva Poland J Taybert, E Pronicka, Warsaw The Netherlands JP Rake, GPA Smit, G Visser, Groningen Turkey H Özen, N Kocak, Ankara

17. Characteristics 288 included patients GSD IaGSD Ib total male-female134 / 9730 / 27164 /124 asian 3 5 8 caucasian 131 33 164 cauc.mediterrean 92 13 105 mixed 5 6 11 Germany 54 13 67 Turkey 43 3 46 Italy 39 7 46 United Kingdom 25 17 42 Poland 10 9 19 Netherlands 17 0 17 other 43 8 51 Rake JP et al EJP 2002

18. microalbuminuria and proteinuria Rake JP et al EJP 2002

19. microalbuminuria and proteinuria Rake JP et al EJP 2002

20. GSD I natural course microalbuminuria prevalence overall 63 / 144 (44%) first detected at median age13 (1- 22) yrs. proteinuria prevalence overall 32 / 242 (13%) first detected at median age16 (1- 25) yrs. Rake JP et al EJP 2002

21. GSD I natural course microalbuminuria prevalence overall 63 / 144 (44%) first detected at median age13 (1- 22) yrs. proteinuria prevalence overall 32 / 242 (13%) first detected at median age16 (1- 25) yrs. hypertension prevalence overall18 / 274 (7%) first detected at median age17 (4 - 42) yrs. Rake JP et al EJP 2002

22. GSD I natural course microalbuminuria prevalence overall 63 / 144 (44%) first detected at median age13 (1- 22) yrs. proteinuria prevalence overall 32 / 242 (13%) first detected at median age16 (1- 25) yrs. hypertension prevalence overall18 / 274 (7%) first detected at median age17 (4 - 42) yrs. creatinine > 2*upper level of normal6 / 288 first detected at median age17 (3 - 40) yrs. hemodialysis3 patients kidney transplantation2 patients Rake JP et al EJP 2002

24. Martens DHL et al 2007

25. GSD I natural course Large kidneys Hyperfiltration Glomerulosclerosis Proteinuria Renal failure Tubular dysfunction Uric acid nephrolithiasis

26. GSD I Tubular dysfunction Proximal: calcium retinol binding protein N-acetyl glucosamine citrate increased Increased decreased Lee P et al 1995, Weinstein DA et al 2001

27. GSD I Tubular dysfunction Distal: incomplete renal tubular acidosis Restaino I et al 1993 Renal stoneshypercalciuria hypocitraturia

28. Hyperuricemia and complications uric acid concentration 0.14 - 0.89 mmol/l xanthine-oxidase inhibitor57% start at median age4.0 yrs (0.2 - 28) hyperuricemia  0.35 (0-5 yrs.); > 0.39 (5-10 yrs.); > 0.45 (10+ yrs.) mmol/l + Allopurinol®29% - Allopurinol®33% Rake JP et al EJP 2002

29. Hyperuricemia and complications uric acid concentration 0.14 - 0.89 mmol/l xanthine-oxidase inhibitor57% start at median age4.0 yrs (0.2 - 28) hyperuricemia  0.35 (0-5 yrs); > 0.39 (5-10 yrs); > 0.45 (10+ yrs) mmol/l + Allopurinol®29% - Allopurinol®33% complications related to hyperuricemia: - renal calcifications / kidney stones (12%) - gouthy arthritis / tophi (4%) Rake JP et al EJP 2002

30. GSD I Renal manifestations Introduction Natural course Renopreservation

31. Diabetic Nephropathy ACE Inhibition: Reduction in microalbuminuria Prevention of increase macroalbuminuria Maintenance of renal function DETAIL 2005, RENAAL 2001, HOPE study 2000.

32. Renopreservation GSD I Nephropathy ACE Inhibition: Reduction in microalbuminuria (>2.5 mg albumin/mmol creatinine)

33. ACE-i Microalbuminuria Melis D et al 2005 95 patients Weinstein DA 8 pat (unpublished) Martens DHL 23 pat (unpublished) No difference 53.423.2 (ns) No difference

34. Renopreservation GSD I Nephropathy ACE Inhibition: Reduction in microalbuminuria Prevention of increase macroalbuminuria

35. Renopreservation GSD I Nephropathy ACE Inhibition: Reduction in microalbuminuria Prevention of increase macroalbuminuria No increase of microalbuminuria

36. Renopreservation GSD I Nephropathy ACE Inhibition: Reduction in microalbuminuria Prevention of macroalbuminuria Maintenance of renal function

37. Martens DHL et al 2007

39. Renopreservation Without ACE inhibition peak at 12-15 yrs: GFR 196 ± 55 ml/min/1,73m 2 24-27 yrs: GFR 115 ± 23 ml/min/1,73m 2 decline 7 ml/min/yr With ACE inhibition peak at 12-15 yrs: GFR 161 ± 36 ml/min/1,73m 2 24-27 yrs: GFR 133 ± 15 ml/min/1,73m 2 decline 2 ml/min/yr Martens DHL et al 2007

40. CGDF versus UCCS CGDFUCCS Microalbuminur ia 3/678/28* Proteinuria 1/797/39* Martens DHL et al 2007

41. Renopreservation ACE inhibition ? Dietary treatment Nocturnal gastric drip Protein restriction

42. GSD I Renal manifestations Introduction Natural course Renopreservation Pregnancy

44. GFR before/after pregnancy 0 20 40 60 80 100 120 140 160 180 200 before pregnancyafter pregnancy period GFR (ml/min/1,73m2) patient 2.1 patient 2.2 patient 3 patient 4 Martens DHL et al 2007 GFR before and after pregnancy

45. GSD I Renal manifestations Introduction Natural course Renopreservation Pregnancy Pathophysiology

46. ROS = Reactive Oxydation Species Diabetes type I Wolf G. et al EJCI 2004

47. Diabetes type I

48. ROS = Reactive Oxydation Species GSD I Glucose-6P Wolf G. et al EJCI 2004

49. GSD I Glucose-6P

53. GSD I kidney TGFβControl kidney TGFβ Urushihara M et al 2004

54. Oxidative stress in GSD Ia kidney Yiu et al 2009

55. GSD I kidney TGFβControl kidney TGFβ Urushihara M et al 2004 ACE Inhibition

56. Glucose-6P

57. Renopreservation ACE inhibition ? Dietary treatment Nocturnal gastric drip Protein restriction

58. Renopreservation ACE inhibition ? Decrease in TGF-β expression Dietary treatment Nocturnal gastric drip Protein restriction

59. GSD I Renal manifestations Introduction Natural course Renopreservation Pregnancy Pathophysiology Conclusions

60. Glomerular function Tubular functions Glomerulosclerosis Pregnancy? Hypercalciuria Hyperuricaemia Hypocitraturia

61. Conclusions ACE inhibition Dietary treatment Pharmacological treatment Renopreservative effects Nocturnal gastric drip Moderate protein restriction Allopurinol Citrate

64. Citrate suppl EXCESS PROTEIN Dieet effecten

65. osteopenia complications related to osteopenia reported infrequently: multiple path. fractures2 patients single path. fracture1 patient rickets2 patients severe scoliosis1 patient Rake JP et al EJP 2002

67. osteopenia complications related to osteopenia reported infrequently: multiple path. fractures2 patients single path. fracture1 patient rickets2 patients severe scoliosis1 patient calcium supplementation25% (32% of lactose-restriction) start at median age4.0 yrs (0.4 - 42) mean daily dose13.7 mg/kg (3 - 50) Rake JP et al EJP 2002

69. Characteristics 288 included patients median age number at latest follow-up Ia 231 10.4 yrs. (0.4 - 45.4) Ib 57 8.7 yrs. (0.4 - 30.6) age (yrs.) at latest follow-up 15-2020-2525-30>30tot Ia 32 19 18 473 Ib 11 2 1 115 Rake JP et al EJP 2002

71. GSD I Kidney Urushihara M et al 2004