Nefro-urologische complicaties: wat is nieuw in ......Nefro-urologische complicaties: wat is nieuw in behandeling en follow-up? Bert Bammens IG Nefrologie Tubereuze sclerose van kind

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?



follow-up?

Bert Bammens

IG Nefrologie



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


Kingswood et al. ASN 2015


Renal in TSC







Renal manifestations: effect on outcome

Kingswood et al.

2012 Recommendations on

follow-up and management:

what about the kidney?



follow-up?

Bert Bammens

IG Nefrologie



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


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


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


MRI abdomen

large (9cm!) angiomyoma “invades” posteromedial part of right

kidney and reaches renal sinus

fat-poor lesion!

“Renal” follow-up after diagnosis


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


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



facial angiofibroma

1y follow-up MRI abdomen


24mm fat-poor lesion right kidney

Case: male, 16y

TSC 2 mutation



facial angiofibroma




0.3 cm growth in one year and fat-poor

Case: male, 16y

TSC 2 mutation



facial angiofibroma




0.3 cm growth in one year and fat-poor

angiomyo(lipo)ma?

oncocytoma?

RCC?



followed by proper histological staining and assessment



FOCUS ON

angiomyolipoma growth!

bleeding risk

preservation of functional renal tissue!

2012 Recommendations on

follow-up and management:

what about the kidney?



follow-up?

Bert Bammens

IG Nefrologie



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


largest lesion left side

66x55x38mm

largest lesion right side

31x17x35mm

prominent vascular component!


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






neuronaldysfunc on

mTORinhibitors



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






neuronaldysfunc on

mTORinhibitors



OO OHO OO

NOO

OO

OH

OH

O

RAD001(Everolimus)

OO OHO OO

NOO

O O

O

OH

OOH

mTORi

30-53% volume reduction


mTOR

inhibition

everolimus






neuronaldysfunc on

mTORinhibitors



OO OHO OO

NOO

OO

OH

OH

O

RAD001(Everolimus)

OO OHO OO

NOO

O O

O

OH

OOH

mTORi


42-53% >50% volume reduction


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





Core phase of study:

database lock at 6 months after randomization of last patient

42% vs. 0% >50% volume reduction P<0.0001




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

Bissler et al. Lancet 2013


SAFETY DATA

mTOR

inhibition

amenhorroea 13 vs. 4%

Case: female, 20y 21y

Side effects mild aphtous stomatitis (temporarily)

mild acne-like skin lesions (temporarily)

hypercholesterolemia (R/ statin)

no amenhorroea


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


mTOR inhibition and angiomyolipomaOpen-label extension phase of EXIST-2:




Open-label extension phase of EXIST-2: SAFETY DATA



Open-label extension phase of EXIST-2: SAFETY DATA

no renal bleeding

proteinuria in some

no clear effect on GFR decline

20 Sept 2012

Case: female, 20y

MRI abdomen


largest lesion left side

66x55x38mm

largest lesion right side

31x17x35mm

prominent vascular component!


Case: female, 18y


MRI abdomen

large (9cm!) angiomyoma “invades” posteromedial part of right

kidney and reaches renal sinus

fat-poor lesion!

Documents

Nefro-urologische complicaties: wat is nieuw in ......Nefro-urologische complicaties: wat is nieuw in behandeling en follow-up? Bert Bammens IG Nefrologie Tubereuze sclerose van kind