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

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

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 ++• 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. et al EJCI 2004

Focal Segmental Glomerulosclerosis

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

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

Participants ESGSDAustria W Endres, D Skladal, InnsbruckBelgium E Sokal, BrusselsCzech Republic J Zeman, PraqueFrance Ph Labrune, ClamartGermany P Bührdel, Leipzig

K Ullrich, Münster (Hamburg)G Däublin, U Wendel, Düsseldorf

Great Britain P Lee, JV Leonard, G Mieli-Vergani, LondonHungary L Szönyi, BudapestItaly P Gandullia, R Gatti, M di Rocco,Genova

D Melis, G Andria, NapoliIsrael S Moses, BeershevaPoland J Taybert, E Pronicka, WarsawThe Netherlands JP Rake, GPA Smit, G Visser, GroningenTurkey H Özen, N Kocak, Ankara

Characteristics 288 included patients GSD Ia GSD Ib total

male-female 134 / 97 30 / 27 164 /124

asian 3 5 8caucasian 131 33 164cauc.mediterrean 92 13 105mixed 5 6 11

Germany 54 13 67Turkey 43 3 46Italy 39 7 46United Kingdom 25 17 42Poland 10 9 19Netherlands 17 0 17

other 43 8 51

Rake JP et al EJP 2002

microalbuminuria and proteinuria

0

10

20

30

40

50

60

70

80

90

100

5- 7 9 11 13 15 17 19 21 23 25+

age (years)

pre

vale

nce

(%

)

microalbuminuria

Rake JP et al EJP 2002

microalbuminuria and proteinuria

0

10

20

30

40

50

60

70

80

90

100

5- 7 9 11 13 15 17 19 21 23 25+

age (years)

pre

vale

nce

(%

)

microalbuminuria

proteinuria

Rake JP et al EJP 2002

GSD I natural coursemicroalbuminuria

prevalence overall 63 / 144 (44%)first detected at median age 13 (1- 22) yrs.

proteinuria prevalence overall 32 / 242 (13%)

first detected at median age 16 (1- 25) yrs.

Rake JP et al EJP 2002

GSD I natural coursemicroalbuminuria

prevalence overall 63 / 144 (44%)first detected at median age 13 (1- 22) yrs.

proteinuria prevalence overall 32 / 242 (13%)first detected at median age 16 (1- 25) yrs.

hypertension prevalence overall 18 / 274 (7%)first detected at median age 17 (4 - 42) yrs.

Rake JP et al EJP 2002

GSD I natural coursemicroalbuminuria

prevalence overall 63 / 144 (44%)first detected at median age 13 (1- 22) yrs.

proteinuria prevalence overall 32 / 242 (13%)first detected at median age 16 (1- 25) yrs.

hypertension prevalence overall 18 / 274 (7%)first detected at median age 17 (4 - 42) yrs.

creatinine > 2*upper level of normal 6 / 288 first detected at median age 17 (3 - 40) yrs.hemodialysis 3 patients

kidney transplantation 2 patients

Rake JP et al EJP 2002

Rake JP et al EJP 2002

Martens DHL et al 2007

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

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 1993

Renal stones hypercalciuria

hypocitraturia

Hyperuricemia and complications

uric acid concentration 0.14 - 0.89 mmol/l

xanthine-oxidase inhibitor 57% start at median age 4.0 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

Hyperuricemia and complicationsuric acid concentration 0.14 - 0.89 mmol/l

xanthine-oxidase inhibitor 57% start at median age 4.0 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

GSD I Renal manifestations

• Introduction

• Natural course

• Renopreservation

Renopreservation

• Diabetic NephropathyACE Inhibition:

Reduction in microalbuminuriaPrevention of increase macroalbuminuriaMaintenance of renal function

DETAIL 2005, RENAAL 2001, HOPE study 2000.

Renopreservation

• GSD I NephropathyACE Inhibition:

Reduction in microalbuminuria

(>2.5 mg albumin/mmol creatinine)

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 NephropathyACE Inhibition:

Reduction in microalbuminuriaPrevention of increase macroalbuminuria

Renopreservation

• GSD I NephropathyACE Inhibition:

Reduction in microalbuminuriaPrevention of increase macroalbuminuria

No increase of microalbuminuria

Renopreservation

• GSD I NephropathyACE Inhibition:

Reduction in microalbuminuriaPrevention of macroalbuminuriaMaintenance of renal function

Martens DHL et al 2007

Martens DHL et al 2007

Renopreservation

Without ACE inhibition

• peak at 12-15 yrs: GFR 196 ± 55

ml/min/1,73m2

• 24-27 yrs: GFR 115 ± 23

ml/min/1,73m2

• decline 7 ml/min/yr

With ACE inhibition

• peak at 12-15 yrs: GFR 161 ± 36

ml/min/1,73m2

• 24-27 yrs: GFR 133 ± 15 ml/min/1,73m2

• decline 2 ml/min/yr

Martens DHL et al 2007

CGDF versus UCCS

CGDF UCCS

Microalbuminuria

3/67 8/28*

Proteinuria 1/79 7/39*

Martens DHL et al 2007

Renopreservation

• ACE inhibition ?

• Dietary treatment Nocturnal gastric drip

Protein restriction

GSD I Renal manifestations

• Introduction

• Natural course

• Renopreservation

• Pregnancy

GFR before/after pregnancy

0

20

40

60

80

100

120

140

160

180

200

before pregnancy after pregnancy

period

GF

R (

ml/m

in/1

,73m

2)

patient 2.1

patient 2.2

patient 3

patient 4

Martens DHL et al 2007

GFR before and after pregnancy

GSD I Renal manifestations

• Introduction

• Natural course

• Renopreservation

• Pregnancy

• Pathophysiology

ROS = Reactive Oxydation Species

Diabetes type I

Wolf G. et al EJCI 2004

Diabetes type I

ROS = Reactive Oxydation Species

GSD I

Glucose-6P

Wolf G. et al EJCI 2004

GSD I

Glucose-6P

Glucose-6P

Glucose-6P

GSD I kidney TGFβ Control kidney TGFβ

Urushihara M et al 2004

Oxidative stress in GSD Ia kidney

Yiu et al 2009

GSD I kidney TGFβ Control kidney TGFβ

Urushihara M et al 2004ACE Inhibition

Glucose-6P

Renopreservation

• ACE inhibition ?

• Dietary treatment Nocturnal gastric drip

Protein restriction

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

Conclusions

• Glomerular function

• Tubular functions

• Glomerulosclerosis• Pregnancy?

• Hypercalciuria• Hyperuricaemia • Hypocitraturia

Conclusions

• ACE inhibition

• Dietary treatment

• Pharmacological treatment

• Renopreservative effects

• Nocturnal gastric drip • Moderate protein

restriction

• Allopurinol• Citrate

• Citrate suppl• EXCESS PROTEIN• Dieet effecten

osteopenia

complications related to osteopenia reportedinfrequently: multiple path. fractures 2 patients

single path. fracture 1 patient

rickets 2 patientssevere scoliosis 1

patient

Rake JP et al EJP 2002

osteopenia

complications related to osteopenia reportedinfrequently: multiple path. fractures 2 patients

single path. fracture 1 patientrickets 2 patientssevere scoliosis 1 patient

calcium supplementation25% (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 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-up15-20 20-25 25-30 >30

totIa 32 19 18 4

73Ib 11 2 1 115

Rake JP et al EJP 2002

GSD I Kidney

Urushihara M et al 2004