View
12
Download
0
Category
Preview:
Citation preview
Nefro-urologische complicaties:
wat is nieuw in behandeling en
follow-up?
Bert Bammens
IG Nefrologie
Tubereuze sclerose van kind tot volwassene:
een ziekte met vele gezichten
How much kidney in TSC?
Nefro-urologische complicaties:
wat is nieuw in behandeling en
follow-up?
Bert Bammens
IG Nefrologie
Tubereuze sclerose van kind tot volwassene:
een ziekte met vele gezichten
TSC (clinical) diagnostic criteria
Northrup et al. Pediatr Neurol 49: 243-254, 2013
Definite: two major OR one major + ≥ 2 minor
Possible: one major OR ≥ 2 minor
TSC (clinical) diagnostic criteria
Definite: two major OR one major + ≥ 2 minor
Possible: one major OR ≥ 2 minor
Major 11. Angiomyolipomas (≥ 2)
Minor 5. Multiple renal cysts
Northrup et al. Pediatr Neurol 49: 243-254, 2013
Renal manifestations of TSC
Van Hoeve et al. ESPN 2015
LONG-TERMRENALOUTCOMEOFALARGECOHORTOFPATIENTSWITHTUBEROUS
SCLEROSISCOMPLEXVanHoeveK,DeWaeleL,JanssensP,ClaesK,LevtchenkoE,BammensB,JansenA,MekahliD
2012 Recommendations on
follow-up and management:
what about the kidney?
Nefro-urologische complicaties:
wat is nieuw in behandeling en
follow-up?
Bert Bammens
IG Nefrologie
Tubereuze sclerose van kind tot volwassene:
een ziekte met vele gezichten
2012 International TSC Consensus Conference
Krueger et al. Pediatr Neurol 49: 255-265, 2013
14-15 June 2012, 79 specialists, 14 countries
12 subcommittees each led by a clinician
Initial “renal” work-up
Krueger et al. Pediatr Neurol 49: 255-265, 2013
Abdominal imaging: MRI preferred over CT or US
Blood pressure assessment
Assessment of renal function
(plasma creatinin, eGFR, cystatin C)
MRI preferred over CT or US
Halpenny et al. Clin Radiol 65: 99-108, 2010
Angiomyolipoma may be fat-poor and missed by CT or US.
angiomyo(lipo)ma
Case: female, 18y
Halpenny et al. Clin Radiol 65: 99-108, 2010
TSC 2 mutation
mental retardation
epilepsy, typical cerebral lesions
retinal facoma
cardial rhambomyoma
US abdomen
small nodular hyperreflective lesions:
angiomyolipoma or small cysts
largest lesion right side 19mm, left side 10mm
Case: female, 18y
Halpenny et al. Clin Radiol 65: 99-108, 2010
MRI abdomen
large (9cm!) angiomyoma “invades” posteromedial part of right
kidney and reaches renal sinus
fat-poor lesion!
“Renal” follow-up after diagnosis
Krueger et al. Pediatr Neurol 49: 255-265, 2013
prenatal / early infancy
(< 24 months)
Renal or liver angiomyolipomas
Dermatological and dental manifestations: hypomelanotic macules, facial angiofibromas, forehead plaque,
shagreen patch, dental pits, intraoral fibroma
CNS lesions / seizures / behavioral issues / mental retardation
early childhood
(< 5yrs)
teenagers(5–18 yrs)
adults(> 18 yrs)
Retinal hamartomas
adults(> 40 yrs)
LAM
Cardiac rhabdomyomas
continued
follow-up
throughout
adulthood
cumulative
nature of
renal lesions
Case: male, 16y
TSC 2 mutation
epilepsy, typical cerebral lesions
bilateral renal cysts
facial angiofibroma
MRI abdomen
multiple renal cysts
21mm fat-poor lesion right kidney, most probably angiomyo(lipo)ma
Case: male, 16y
TSC 2 mutation
epilepsy, typical cerebral lesions
bilateral renal cysts
facial angiofibroma
1y follow-up MRI abdomen
multiple renal cysts
24mm fat-poor lesion right kidney
Case: male, 16y
TSC 2 mutation
epilepsy, typical cerebral lesions
bilateral renal cysts
facial angiofibroma
1y follow-up MRI abdomen
multiple renal cysts
24mm fat-poor lesion right kidney
0.3 cm growth in one year and fat-poor
Case: male, 16y
TSC 2 mutation
epilepsy, typical cerebral lesions
bilateral renal cysts
facial angiofibroma
1y follow-up MRI abdomen
multiple renal cysts
24mm fat-poor lesion right kidney
0.3 cm growth in one year and fat-poor
angiomyo(lipo)ma?
oncocytoma?
RCC?
“Renal” follow-up after diagnosis
Krueger et al. Pediatr Neurol 49: 255-265, 2013
followed by proper histological staining and assessment
“Renal” follow-up after diagnosis
Krueger et al. Pediatr Neurol 49: 255-265, 2013
FOCUS ON
angiomyolipoma growth!
bleeding risk
preservation of functional renal tissue!
2012 Recommendations on
follow-up and management:
what about the kidney?
Nefro-urologische complicaties:
wat is nieuw in behandeling en
follow-up?
Bert Bammens
IG Nefrologie
Tubereuze sclerose van kind tot volwassene:
een ziekte met vele gezichten
Case: female, 20y
genetics: no TSC1/2 mutation found
facial angiofibromata
cortical tubers
intermittent headache & light-headedness since childhood: E on EEG
bilateral angiomyolipomas
Presenting symptom: gross hematuria and right lumbar pain
Symptomatic treatment by GP and referral to nephrology outpatient clinic
Case: female, 20y
MRI abdomen
bilateral angiomyolipomas
largest lesion left side
66x55x38mm
largest lesion right side
31x17x35mm
prominent vascular component!
Krueger et al. Pediatr Neurol 49: 255-265, 2013
Case: female, 20yAngiography bilateral renal angiogram
R/ selective embolization of
angiomyolipoma with hypertrophic
vascular component (right side)
mTOR inhibition and angiomyolipoma
cellgrowthandprolifera on
angiogenesisandlymphangiogenesis
cellorienta onandmigra on
cellmetabolismandglucoseuptakeSEGA,angiomyolipoma
angiomyolipoma,LAMcor caldysplasia
neuronaldysfunc on
mTORinhibitors
Huberetal.KidneyInt2011
Rapamycin(Sirolimus)
OO OHO OO
NOO
OO
OH
OH
O
RAD001(Everolimus)
OO OHO OO
NOO
O O
O
OH
OOH
mTORi
mTOR
inhibition
sirolimus
cellgrowthandprolifera on
angiogenesisandlymphangiogenesis
cellorienta onandmigra on
cellmetabolismandglucoseuptakeSEGA,angiomyolipoma
angiomyolipoma,LAMcor caldysplasia
neuronaldysfunc on
mTORinhibitors
Huberetal.KidneyInt2011
Rapamycin(Sirolimus)
OO OHO OO
NOO
OO
OH
OH
O
RAD001(Everolimus)
OO OHO OO
NOO
O O
O
OH
OOH
mTORi
30-53% volume reduction
Coombs J Am Ass Nurse Pract 25: 588-596, 2013
mTOR
inhibition
sirolimus
cellgrowthandprolifera on
angiogenesisandlymphangiogenesis
cellorienta onandmigra on
cellmetabolismandglucoseuptakeSEGA,angiomyolipoma
angiomyolipoma,LAMcor caldysplasia
neuronaldysfunc on
mTORinhibitors
Huberetal.KidneyInt2011
Rapamycin(Sirolimus)
OO OHO OO
NOO
OO
OH
OH
O
RAD001(Everolimus)
OO OHO OO
NOO
O O
O
OH
OOH
mTORi
30-53% volume reduction
Coombs J Am Ass Nurse Pract 25: 588-596, 2013
mTOR
inhibition
everolimus
cellgrowthandprolifera on
angiogenesisandlymphangiogenesis
cellorienta onandmigra on
cellmetabolismandglucoseuptakeSEGA,angiomyolipoma
angiomyolipoma,LAMcor caldysplasia
neuronaldysfunc on
mTORinhibitors
Huberetal.KidneyInt2011
Rapamycin(Sirolimus)
OO OHO OO
NOO
OO
OH
OH
O
RAD001(Everolimus)
OO OHO OO
NOO
O O
O
OH
OOH
mTORi
Coombs J Am Ass Nurse Pract 25: 588-596, 2013
42-53% >50% volume reduction
mTOR inhibition and angiomyolipoma
Bissler et al. Lancet 381: 817-824, 2013
double-blind, placebo-controlled, phase 3 RCT
>18y
definite TSC or sporadic LAM 2:1 randomization
≥ 1 angiomyolipoma ≥ 30mm everolimus 10mg per day or placebo
mTOR inhibition and angiomyolipoma
Bissler et al. Lancet 381: 817-824, 2013
Core phase of study:
database lock at 6 months after randomization of last patient
42% vs. 0% >50% volume reduction P<0.0001
mTOR inhibition and angiomyolipoma
Bissler et al. Lancet 381: 817-824, 2013
Core phase of study:
database lock at 6 months after randomization of last patient
Case: female, 20y 21y
MRI abdomen no new lesions
volume reduction of lesions
regression of vascular component
Case: female, 20y 21y
Side effects mild aphtous stomatitis (temporarily)
mild acne-like skin lesions (temporarily)
hypercholesterolemia (R/ statin)
no amenhorroea
mTOR inhibition and angiomyolipoma
Bissler et al. Nephrol Dial Transplant 31: 111-119, 2016
Open-label extension phase of EXIST-2 trial
(from data cutoff 30 June 2011 till 1 May 2013)
everolimus 10mg per day (titrated based on tolerability)
mTOR inhibition and angiomyolipomaOpen-label extension phase of EXIST-2:
N = 112 median exposure 28.9 (0.5-46.2) months
54% >50% volume reduction
Bissler et al. Nephrol Dial Transplant 31: 111-119, 2016
mTOR inhibition and angiomyolipomaOpen-label extension phase of EXIST-2:
Bissler et al. Nephrol Dial Transplant 31: 111-119, 2016
mTOR inhibition and angiomyolipoma
Bissler et al. Nephrol Dial Transplant 31: 111-119, 2016
Open-label extension phase of EXIST-2: SAFETY DATA
mTOR inhibition and angiomyolipoma
Bissler et al. Nephrol Dial Transplant 31: 111-119, 2016
Open-label extension phase of EXIST-2: SAFETY DATA
no renal bleeding
proteinuria in some
no clear effect on GFR decline
Case: female, 20y
MRI abdomen
bilateral angiomyolipomas
largest lesion left side
66x55x38mm
largest lesion right side
31x17x35mm
prominent vascular component!
Krueger et al. Pediatr Neurol 49: 255-265, 2013
Recommended