1. 98 年度第二次南區小兒腎臟學術研討會 98 年度第二次南區小兒腎臟學術研討會 Tuberous Sclerosis Complex with PKD and Renal Hemorrhage 黃雅雲，李青松，邱元佑 國立成功大學醫學院附設醫院小兒部

2. Basic Information Name: 謝 O 珊 Age: 18-year-old Gender: Female Date of Admission: 2009/2/24 Underline disease: tuberous sclerosis complex

3. Underlying Disease Tuberous sclerosis complex Tuberous sclerosis complex Skin: Skin: Facial angiofibromas Facial angiofibromas Hypomelanic macules Hypomelanic macules Forehead plaques Forehead plaques CNS: giant cell astrocytoma s/p operation (91-4) CNS: giant cell astrocytoma s/p operation (91-4) Renal: Bilateral multiple huge angiomyolipomas Renal: Bilateral multiple huge angiomyolipomas

4. Present Illness 02/24 5pm Right flank pain Pattern: dullness and persistent aggravated when walk and deep breath Sharp pain since 7 pm 02/24 7pm No trauma No fever, no dysuria/ frequency/ urgency NCKUH ER

5. Renal Sonography

6. Abdominal CT

8. Hemogram & Biochemistry Estimated blood loss volume: 500-600 ml Estimated blood loss volume: 500-600 ml 02/2402/2502/26 WBC840079007900 Hct38.5%29.8%29% Hb13.410.310.0 Platelet247K188K173K BUNCreaGOTGPTAlbuminCRP120.715104.8 < 7.0 SGPHProteinWBCRBCEpith1.0206.0Negative0-10-113-18

9. Further Condition Transcatheter arterial embolization (TAE) or Nephrectomy  bleeding spontaneous ceased Transferred to general ward on 02/27 & discharged on 03/02

10. Tuberous Sclerosis Complex The majority insults leading to death or disability Neurologic disease – the commonest cause of death in childhood and adolescence Renal disease – angiomyolipomas (60-80%), leading to renal failure or spontaneous hemorrhage Selective transcatheter arterial embolization (TAE) Nephrectomy Pulmonary manifestation – lymphangioleiomyomatosis, a progressive lung disease

11. Tuberous Sclerosis Complex A tumor-suppressor syndrome caused by mutations in the tuberin gene (TSC2) or the hamartin gene (TSC1) The hamartin–tuberin (TSC1-TSC2) complex regulates the activity of the mammalian target of rapamycin (mTOR) mTOR -- lies downstream of cellular pathways controlling cell growth and proliferation (G1  S) Abnormal signaling through mTOR is involved in a number of tumor-suppressor syndromes and cancers

13. Clinical Experience of Rapamycin in Tuberous Sclerosis ) Structure analogous -- Sirolimus 、 CCI-779 (Temsirolimus) 、 RAD001(Everolimus) 、 and FK-50 Case report of sirolimus-induced reduction in angiomyolipoma size clinically was first reported in 2006 19 y/o female patient with bilateral renal angiomyolipoma (tumor size, 5.2 x 6.8 x 7.3 cm) (Am J Kidney Dis 2006;48(3):e27-e29) 38-year-old female with huge angiomyolipoma Left side: 20.5 cm in diameter; right side: 11.5 cm 6 mg of sirolimus once daily for 2 years (Eur J Intern Med 2007;18:76-7)

14. Treatment Effect Before Tx1 year 2 year 6 months after stopping Tx Right side Left side Before 115 mm 205 mm At 1 year 104 mm 126 mm At 2 year 100 mm 120 mm

15. Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex 25 patients, 18 to 65 y/o, from May 2003 to November 2004 All patients received sirolimus for 1 year; followed up for an additional year after stopping medication Image survey were performed at months 2, 4, 6, 12, 18, and 24 MRI for brain and abdomen CT scan for lung N Engl J Med 2008;358:140-51

16. Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex 0.25 mg/m 2 (serum levels prevent rejection in renal transplants) 2 weeks Adjust dose to achieve serum sirolimus level between 1 - 5 ng/ml 2 months Adjust dose to achieve serum sirolimus level between 5-10 ng/ml The longest coronal-plane dimension ↓10% of the baseline value YES NO Keep current dosage 4 10-15 N Engl J Med 2008;358:140-51

17. Result -- A Result -- Angiomyolipoma N Engl J Med 2008;358:140-51

18. Result -- A Result -- Angiomyolipoma 70% of the baseline value 5 of the 18 patients (28%) remained at least 30% smaller than baseline value 1 year after therapy } N Engl J Med 2008;358:140-51

19. Adverse Events

20. Our Patient Start since 2009/03/02 Start Sirolimus (0.25mg/m 2 ) since 2009/03/02 Follow up renal echo Follow up renal echo 03/11: hyperechoic nodules(~5.6cm) in both kidneys 03/11: hyperechoic nodules(~5.6cm) in both kidneys 04/08: hyperechoic nodules(~4.4cm) in both kidneys 04/08: hyperechoic nodules(~4.4cm) in both kidneys 03/1104/08

21. Thanks for your Attention

22. CT scan on August, 2008 8 x 4.5 x 9 cm 3.3 x 3.3 x 4.5 cm Volume: 165 cm Volume: 165 cm 3 Volume: 24.5 cm Volume: 24.5 cm 3

23. Physical Examination Consciousness: clear Consciousness: clear Appearance: fair-looking Appearance: fair-looking Vital sign: Vital sign: T/P/R:36.4°C/ 109 / 14 T/P/R:36.4°C/ 109 / 14 BP: 135/85 mmHg BP: 135/85 mmHg Head: Head: conj: not anemic conj: not anemic sclera: not icteric sclera: not icteric throat: not injected throat: not injected tonsil: not enlarged tonsil: not enlarged Neck: supple, LAP(-) Neck: supple, LAP(-) Chest: symmetric expansion, subcostal retraction (-) Chest: symmetric expansion, subcostal retraction (-) - H.S.: regular heart beat, - H.S.: regular heart beat, no audible murmur no audible murmur - B.S.: clear,no crackles - B.S.: clear,no crackles Abdomen: soft, no distended Abdomen: soft, no distended - Tenderness (+) over right flank area and back - Tenderness (+) over right flank area and back - No rebounding pain - No rebounding pain - L/S: impalpable / impalpable - L/S: impalpable / impalpable - BS: hypoactive - BS: hypoactive Extremities: pitting edema (-) Extremities: pitting edema (-) Skin: turgor fine, rash(+) Skin: turgor fine, rash(+)

24. Renal hemorrhage occurred in 51% of patients with lesions 4.0 cm or larger Current management suggestion: Asymptomatic lesions < 4.0 cm: observation with annual CT scan ≧ 4.0 cm, follow-up CT scans every 6 months Prophylactic embolization of asymptomatic lesions 4.0 cm or larger is recommended in select highrisk patients, including younger women who intend pregnancy or patients in which regularfollow-up is difficult.