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

GSD I Renal manifestations • • • Introduction Natural course Renopreservation Pregnancy Pathophysiology Conclusions GSD I Renal manifestations • • • Introduction Natural course Renopreservation Pregnancy Pathophysiology Conclusions

GSD I Renal manifestations • Introduction GSD I Renal manifestations • Introduction

GSD I • Short stature • Hepatomegaly • Nephromegaly • • Hypoglycemia Lactic acidemia GSD I • Short stature • Hepatomegaly • Nephromegaly • • Hypoglycemia Lactic acidemia Hyperuricemia Hyperlipidemia

J. Y. Chou et al 2007 J. Y. Chou et al 2007

J. Y. Chou et al 2007 J. Y. Chou et al 2007

J. Y. Chou et al 2007 J. Y. Chou et al 2007

J. Y. Chou et al 2007 J. Y. Chou et al 2007

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

GSD I Introduction • • GSD I nephropathy: Large kidneys Hyperperfusion Hyperfiltration Intraglomerular P 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

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

Focal Segmental Glomerulosclerosis Focal Segmental Glomerulosclerosis

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

GSD I Renal manifestations • Introduction • Natural course GSD I Renal manifestations • Introduction • Natural course

European Study on Glycogen ESGSD I Storage Disease type * * - aims: to European Study on Glycogen ESGSD I Storage Disease type * * - 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

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

Characteristics 288 included patients male-female GSD Ia 134 / 97 asian 3 8 caucasian Characteristics 288 included patients male-female GSD Ia 134 / 97 asian 3 8 caucasian 131 cauc. mediterrean 92 mixed 5 11 Germany 67 Turkey Italy 46 United Kingdom GSD Ib 30 / 27 5 33 13 54 43 39 25 total 164 /124 6 164 105 13 3 7 17 46 Rake JP et al EJP 2002

microalbuminuria and proteinuria Rake JP et al EJP 2002 microalbuminuria and proteinuria Rake JP et al EJP 2002

microalbuminuria and proteinuria Rake JP et al EJP 2002 microalbuminuria and proteinuria Rake JP et al EJP 2002

GSD I natural course microalbuminuria prevalence overall first detected at median age 63 / GSD I natural course microalbuminuria prevalence overall first detected at median age 63 / 144 (44%) 13 (1 - 22) yrs. proteinuria prevalence overall first detected at median age 32 / 242 (13%) 16 (1 - 25) yrs. Rake JP et al EJP 2002

GSD I natural course microalbuminuria prevalence overall first detected at median age proteinuria prevalence GSD I natural course microalbuminuria prevalence overall first detected at median age proteinuria prevalence overall first detected at median age hypertension prevalence overall first detected at median age 63 / 144 (44%) 13 (1 - 22) yrs. 32 / 242 (13%) 16 (1 - 25) yrs. 18 / 274 (7%) 17 (4 - 42) yrs. Rake JP et al EJP 2002

GSD I natural course microalbuminuria prevalence overall first detected at median age proteinuria prevalence GSD I natural course microalbuminuria prevalence overall first detected at median age proteinuria prevalence overall first detected at median age hypertension prevalence overall first detected at median age creatinine > 2*upper level of normal first detected at median age hemodialysis kidney transplantation 63 / 144 (44%) 13 (1 - 22) yrs. 32 / 242 (13%) 16 (1 - 25) yrs. 18 / 274 (7%) 17 (4 - 42) yrs. 6 / 288 17 (3 - 40) yrs. 3 patients 2 patients Rake JP et al EJP 2002

Rake JP et al EJP 2002 Rake JP et al EJP 2002

Martens DHL et al 2007 Martens DHL et al 2007

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

GSD I Tubular dysfunction • Proximal: calcium retinol binding protein N-acetyl glucosamine citrate increased 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

GSD I Tubular dysfunction • Distal: incomplete renal tubular acidosis Restaino I et al GSD I Tubular dysfunction • Distal: incomplete renal tubular acidosis Restaino I et al 1993 Renal stones hypercalciuria hypocitraturia

Hyperuricemia and complications uric acid concentration 0. 14 - 0. 89 mmol/l xanthine-oxidase inhibitor Hyperuricemia and complications uric acid concentration 0. 14 - 0. 89 mmol/l xanthine-oxidase inhibitor start at median age 57% 4. 0 yrs (0. 2 - 28) hyperuricemia Ø 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

Hyperuricemia and complications uric acid concentration xanthine-oxidase inhibitor start at median age 0. 14 Hyperuricemia and complications uric acid concentration xanthine-oxidase inhibitor start at median age 0. 14 - 0. 89 mmol/l 57% 4. 0 yrs (0. 2 - 28) hyperuricemia Ø 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

GSD I Renal manifestations • Introduction • Natural course • Renopreservation GSD I Renal manifestations • Introduction • Natural course • Renopreservation

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

Renopreservation • GSD I Nephropathy ACE Inhibition: Reduction in microalbuminuria (>2. 5 mg albumin/mmol Renopreservation • GSD I Nephropathy ACE Inhibition: Reduction in microalbuminuria (>2. 5 mg albumin/mmol creatinine)

ACE-i Microalbuminuria • Melis D et al 2005 95 patients • Weinstein DA 8 ACE-i Microalbuminuria • Melis D et al 2005 95 patients • Weinstein DA 8 pat (unpublished) • Martens DHL 23 pat (unpublished) • No difference • 53. 4 23. 2 (ns) • No difference

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

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

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

Martens DHL et al 2007 Martens DHL et al 2007

Martens DHL et al 2007 Martens DHL et al 2007

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

CGDF versus UCCS CGDF Microalbuminur 3/67 ia Proteinuria 1/79 UCCS 8/28* 7/39* Martens DHL CGDF versus UCCS CGDF Microalbuminur 3/67 ia Proteinuria 1/79 UCCS 8/28* 7/39* Martens DHL et al 2007

Renopreservation • ACE inhibition ? • Dietary treatment Nocturnal gastric drip Protein restriction Renopreservation • ACE inhibition ? • Dietary treatment Nocturnal gastric drip Protein restriction

GSD I Renal manifestations • • Introduction Natural course Renopreservation Pregnancy GSD I Renal manifestations • • Introduction Natural course Renopreservation Pregnancy

GFR before and after pregnancy GFR before/after pregnancy 200 GFR (ml/min/1, 73 m 2) GFR before and after pregnancy GFR before/after pregnancy 200 GFR (ml/min/1, 73 m 2) 180 160 140 120 patient 2. 1 patient 2. 2 100 patient 3 patient 4 80 60 40 20 0 before pregnancy after pregnancy period Martens DHL et al 2007

GSD I Renal manifestations • • • Introduction Natural course Renopreservation Pregnancy Pathophysiology GSD I Renal manifestations • • • Introduction Natural course Renopreservation Pregnancy Pathophysiology

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

Diabetes type I Diabetes type I

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

GSD I Glucose-6 P GSD I Glucose-6 P

Glucose-6 P Glucose-6 P

Glucose-6 P Glucose-6 P

GSD I kidney TGFβ Control kidney TGFβ Urushihara M et al 2004 GSD I kidney TGFβ Control kidney TGFβ Urushihara M et al 2004

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

GSD I kidney TGFβ ACE Inhibition Control kidney TGFβ Urushihara M et al 2004 GSD I kidney TGFβ ACE Inhibition Control kidney TGFβ Urushihara M et al 2004

Glucose-6 P Glucose-6 P

Renopreservation • ACE inhibition ? • Dietary treatment Nocturnal gastric drip Protein restriction Renopreservation • ACE inhibition ? • Dietary treatment Nocturnal gastric drip Protein restriction

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

GSD I Renal manifestations • • • Introduction Natural course Renopreservation Pregnancy Pathophysiology Conclusions GSD I Renal manifestations • • • Introduction Natural course Renopreservation Pregnancy Pathophysiology Conclusions

Conclusions • Glomerular function • Glomerulosclerosis • Pregnancy? • Tubular functions • Hypercalciuria • Conclusions • Glomerular function • Glomerulosclerosis • Pregnancy? • Tubular functions • Hypercalciuria • Hyperuricaemia • Hypocitraturia

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

• Citrate suppl • EXCESS PROTEIN • Dieet effecten • Citrate suppl • EXCESS PROTEIN • Dieet effecten

osteopenia complications related to osteopenia reported infrequently: multiple path. fractures 2 patients single path. osteopenia complications related to osteopenia reported infrequently: multiple path. fractures 2 patients single path. fracture 1 patient rickets 2 patients severe scoliosis 1 patient Rake JP et al EJP 2002

osteopenia complications related to osteopenia reported infrequently: multiple path. fractures single path. fracture rickets osteopenia complications related to osteopenia reported infrequently: multiple path. fractures single path. fracture rickets severe scoliosis 2 patients 1 patient calcium supplementation 25% (32% of lactose-restriction) start at median age 4. 0 yrs (0. 4 - 42) mean daily dose 13. 7 mg/kg (3 - 50) Rake JP et al EJP 2002

Characteristics 288 included patients median age at latest follow-up 10. 4 yrs. (0. 4 Characteristics 288 included patients median age at latest follow-up 10. 4 yrs. (0. 4 - 45. 4) 8. 7 yrs. (0. 4 - 30. 6) Ia Ib number 231 57 Ia age (yrs. ) at latest follow-up 15 -20 20 -25 25 -30 >30 32 19 18 Ib 73 11 2 1 1 4 tot 15 Rake JP et al EJP 2002

GSD I Kidney Urushihara M et al 2004 GSD I Kidney Urushihara M et al 2004