diagnosis and treatment of renal manifestations in gsd i g.p.a. smit beatrix children’s hospital...
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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