Renal Manifestations of Tuberous Sclerosis Complex

Main Article Content

Nikhil Nair
Ronith Chakraborty
Zubin Mahajan
Aditya Sharma
Sidarth K. Sehti
Rupesh Raina

Keywords

Abstract

Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors and seizures. TSC can manifests in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.

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References

1. Schepis, C. “The tuberous sclerosis complex,” in Dermatological Cryosurgery and Cryotherapy, eds W. Abramovits, G. Graham, Y. Har-Shai, and R. Strumia (London: Springer), 615–617. http://dx.doi.org/10.1007/978-1-4471-6765-5_120
2. Javaid A, Zeshan S, Islah Ud. Tuberous sclerosis. J Pak Med Assoc. 2019;69(3):445.
3. Rakowski SK, Winterkorn EB, Paul E, Steele DJR, Halpern EF, Thiele EA. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006;70(10):1777–82. http://dx.doi.org/10.1038/sj.ki.5001853
4. Leung AKC, Robson WLM. Tuberous sclerosis complex: A review. J Pediatr Health Care. 2007;21(2):108–14. http://dx.doi. org/10.1016/j.pedhc.2006.05.004
5. Plank TL, Yeung RS, Henske EP. Advances in brief Hiimartin, the product of the tuberous sclerosis l (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res. 1998;58(21):4766–70.
6. Slegtenhorst MV, Nellist M, Nagelkerken M, Cheadle J, Snell Ru, Ouweland AVD, et al. Interaction between Hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol. 1998;7(6):1053–7. http://dx.doi.org/10.1093/hmg/7.6.1053
7. Cheadle J, Reeve M, Sampson J, Kwiatkowski DJ. Molecular genetic advances in tuberous sclerosis. Hum Genet. 2000;107:97– 114. http://dx.doi.org/10.1007/s004390000348
8. Jones AC, Shyamsundar MM, Thomas MW, et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous scle-rosis. Am J Hum Genet. 1999;64(5):1305–15. http://dx.doi. org/10.1086/302381
9. Dabora SL, Jozwiak S, Franz DN, Roberts, PS, Nieto, A, Chung, J. et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet. 2001;68(1):64–80. http:dx.doi.org/10.1086/316951
10. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243–54. http:dx.doi. org/10.1016/j.pediatrneurol.2013.08.001
11. Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):255–65. http://dx.doi. org/10.1016/j.pediatrneurol.2013.08.002
12. Calcagnì A, Kors L, Verschuren E, Cegli RD, Zampelli N, Nusco E, et al. Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling. ELife. 2016 Sept;5:1– 26. http://dx.doi.org/10.7554/eLife.17047
13. Seyam R, AlKhudair W, Kattan S, Alotaibi M, Alzahrani H, Waleed A. The risks of renal angiomyolipoma: Reviewing the evidence. J Kidney Cancer VHL. 2017;4(4):13–25. http://dx.doi. org/10.15586/jkcvhl.2017.97
14. Kingswood CJ, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, et al. Renal angiomyolipoma in patients with tuber-ous sclerosis complex: Findings from the TuberOus SClerosis Registry to increase disease awareness. Nephrol Dial Transpl. 2019;34(3):502–8. http://dx.doi.org/10.1093/ndt/gfy063
15. Kingswood CJ, Bolton P, Crawford P, Harland P, Johnson SR, Sampson JR, et al. The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the clinical practice research datalink (CPRD). Eur J Paediatr Neuro. 2016;20(2):296–308. http://dx.doi.org/10.1016/j. ejpn.2015.11.011
16. Eijkemans MJ, van der Wal W, Reijnders LJ, Roes KC, van Waalwijk van Doorn-Khosrovani SB, Pelletier C, et al. Long-term follow-up assessing renal angiomyolipoma treatment patterns, morbidity, and mortality: An observational study in tuberous sclerosis complex patients in the Netherlands. Am J Kidney Dis. 2015;66(4):638–45. http://dx.doi.org/10.1053/j. ajkd.2015.05.016
17. Klein KO, Baron J, Colli MJ, McDonnell DP, Cutler GB Jr. Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. So J Clin Invest. 1994;94(6):247. http://dx.doi.org/10.1172/JCI117616
18. Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES. Renal lesion growth in children with tuberous sclerosis com-plex. J Urol. 1998;160(1):141. http://dx.doi.org/10.1016/ S0022-5347(01)63072-6
19. Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti  PE. Comas: The past, the present and the future. Virchows Arch. 2008 Feb;452(2):119–32. http://dx.doi.org/10.1007/ s00428-007-0509-1
20. Basch ML, García-Castro MI, Bronner-Fraser M. Molecular mechanisms of neural crest induction. Birth Defects Res C. 2004;72(2):109–23. http://dx.doi.org/10.1002/bdrc.20015
21. Henske EP. Metastasis of benign tumor cells in tuberous scle-rosis complex. Genes Chromosom Cancer. 2003;38(4):376–81. http://dx.doi.org/10.1002/gcc.10252
22. Yue M, Pacheco G, Cheng T, Li J, Wang Y, Henske EP, et al. Evidence supporting a lymphatic endothelium ori-gin for angiomyolipoma, a TSC2 ? Tumor related to lymphangioleiomyomatosis. Am J Pathol. 2016;186(7):1825–36. http://dx.doi.org/10.1016/j.ajpath.2016.03.009
23. Schneider G, Schmidt-Supprian M, Rad R, Saur D. Tissue-specific tumorigenesis: Context matters. Nat Rev Cancer. 2017;17(4):239–53. http://dx.doi.org/10.1038/nrc.2017.5
24. Koichiro Y, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M. Renal angiomyolipoma: Relationships between tumor size, aneurysm formation, and rupture. Radiology. 2002;225(1): 78–82. http://dx.doi.org/10.1148/radiol.2251011477
25. Shepard CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc. 1991;66(8): 792–6. http://dx.doi.org/10.1016/S0025-6196(12)61196-3
26. Beltramello A, Puppini G, Bricolo A, Andreis IAB, El-Dalati G, Longa L, et al. Does the tuberous sclerosis complex include intracranial aneurysms? A case report with a review of the literature. Pediatr Radiol. 1999;29(3):206–11. http://dx.doi. org/10.1007/s002470050573
27. Jing Z, Brugarolas J, Parada LF. Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activat-ing MTORC1. Hum Mol Genet. 2009;18(22):4428–41. http:// dx.doi.org/10.1093/hmg/ddp398
28. Yang M, Liu E, Tang L, Lei Y, Sun X, Hu J, et al. Emerging roles and regulation of MiT/TFE transcriptional factors. Cell Commun Signal. 2018;16(1):1–11. http://dx.doi.org/10.1186/ s12964-018-0242-1
29. Badenas C, Torra R, Pérez-Oller L, Mallolas J, Talbot-Wright R, Torregrosa V, et al. Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients. Eur J Hum Genet. 2000;8(7):487–92. http://dx.doi.org/10.1038/sj.ejhg.5200484
30. Brasier JL, Henske EP. Loss of the polycystic kidney dis-ease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J Clin Invest. 1997;99(2):194–9. http://dx.doi.org/10.1172/JCI119147
31. Wilson C, Bonnet C, Guy C, Idziaszczyk S, Colley J, Humphreys  V, et al. Tsc1 haploinsufficiency without mamma-lian target of rapamycin activation is sufficient for renal cyst for-mation in Tsc1+/- mice. Cancer Res. 2006;66(16):7934–8. http:// dx.doi.org/10.1158/0008-5472.CAN-06-1740
32. Bonsib SM, Boils C, Gokden N, Grignon D, Gu X, Higgins JPT et al. Tuberous sclerosis complex: Hamartin and tuberin expres-sion in renal cysts and its discordant expression in renal neo-plasms. Pathol Res Pract. 2016;212(11):972–9. http://dx.doi. org/10.1016/j.prp.2016.04.005
33. Cox RL, Calderon de Anda F, Mangoubi T, Yoshii A. Multiple critical periods for rapamycin treatment to correct structural defects in Tsc-1-suppressed brain. Front Mol Neurosci. 2018;11:409. http://dx.doi.org/10.3389/fnmol.2018.00409
34. Dhakal M, Dhakal OP, Bhandari D. Polycystic kidney disease and chronic renal failure in tuberous sclerosis. BMJ Case Rep. 2013 Oct 2;2013:bcr2013200711. http://dx.doi.org/10.1136/ bcr-2013-200711
35. Huber TB, Walz G, Kuehn EW. mTOR and rapamycin in the kidney: Signaling and therapeutic implications beyond immu-nosuppression. Kidney Int. 2011 Mar 1;79(5):502–11. http://dx. doi.org/10.1038/ki.2010.457
36. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. PNAS. 2006 Apr 4;103(14):5466–71. http://dx.doi.org/10.1073/pnas.0509694103
37. Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – A contiguous gene syndrome. Nat Genet. 1994 Dec;8(4):328–32. http://dx.doi.org/10.1038/ng1294-328
38. Bisceglia M, Galliani C, Carosi I, Simeone A, Ben-Dor D. Tuberous sclerosis complex with polycystic kidney disease of the adult type: The TSC2/ADPKD1 contiguous gene syn-drome. Int J Surg Pathol. 2008 Oct;16(4):375–85. http://dx.doi. org/10.1177/1066896908319578
39. Gullerova M, Proudfoot NJ. Cohesin complex promotes tran-scriptional termination between convergent genes in S. pombe. Cell. 2008 Mar 21;132(6):983–95. http://dx.doi.org/10.1016/j. cell.2008.02.040
40. Qian F, Watnick TJ, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996 Dec 13;87(6):979–87. http://dx.doi.org/10.1016/S0092-8674(00)81793-6
41. Longa L, Brusco A, Carbonara C, Polidoro S, Scolari F. A tuberous sclerosis patient with a large TSC2 and PKD1 gene deletion shows extrarenal signs of autosomal dominant polycystic kidney disease. Contrib Nephrol. 1997;122:91–5. http:// dx.doi.org/10.1159/000059909
42. Sampson JR, Maheshwar MM, Aspinwall R, Thompson P, Cheadle JP, Ravine D, et al. Renal cystic disease in tuberous scle-rosis: Role of the polycystic kidney disease 1 gene. Am J Hum Genet. 1997 Oct;61(4):843. http://dx.doi.org/10.1086/514888
43. Oesterling JE, Fishman EK, Goldman SM, Marshall FF. The management of renal angiomyolipoma. J Urol. 1986 Jun;135(6):1121–4. http://dx.doi.org/10.1016/S0022-5347(17)46013-7
44. Pirson Y. Tuberous sclerosis complex-associated kidney angiomyolipoma: From contemplation to action. Nephrol Dial Transpl. 2013 Jul 1;28(7):1680–5. http://dx.doi.org/10.1093/ndt/gft009
45. Neumann HP, Brüggen V, Berger DP, Herbst E, Blum U, Morgenroth A, et al. Tuberous sclerosis complex with end-stage renal failure. Nephrol Dial Transpl. 1995 Mar 1;10(3):349–53.
46. Manno C, Claudatus J, La Raia E, Savino L, Schena FP. Chronic renal failure for bilateral spontaneous kidney rupture in a case of tuberous sclerosis. Am J Nephrol. 1991;11(5):416–21. http://dx.doi.org/10.1159/000168349
47. Brugarolas J, Kaelin WG Jr. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell. 2004 Jul 1;6(1):7–10. http://dx.doi.org/10.1016/j.ccr.2004.06.020
48. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG Jr. TSC2 regulates VEGF through mTOR-dependent and-indepen-dent pathways. Cancer Cell. 2003 Aug 1;4(2):147–58. http://dx. doi.org/10.1016/S1535-6108(03)00187-9
49. Yoder BK. Role of primary cilia in the pathogenesis of polycys-tic kidney disease. J Am Soc Nephrol. 2007 May 1;18(5):1381–8. http://dx.doi.org/10.1681/ASN.2006111215
50. Kugoh H, Kleymenova E, Walker CL. Retention of membrane-localized ?-catenin in cells lacking functional polycystin-1 and tuberin. Mol Carcinog. 2002 Mar;33(3):131–6. http://dx.doi. org/10.1002/mc.10034
51. Huan Y, van Adelsberg J. Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins. J Clin Invest. 1999 Nov 15;104(10):1459–68. http://dx.doi.org/10.1172/ JCI5111
52. Al-Saleem T, Wessner LL, Scheithauer BW, Patterson K, Roach ES, Dreyer SJ et al. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer. 1998;83(10):2208–16. http://dx.doi. org/10.1002/(SICI)1097-0142(19981115)83:10%3C2208::AID-CNCR21%3E3.0.CO;2-K
53. Bjornsson J, Short MP, Kwiatkowski DJ, Henske EP. Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol. 1996;149:1201–8.
54. Yang P, Cornejo KM, Sadow PM, Cheng, L, Wang, M, Xiao, Y., et al. Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol. 2014;38(7):895–909. http://dx.doi.org/10.1097/ PAS.0000000000000237
55. Malaga-Dieguez L, Spencer R, Pehrson LJ, Vento, S, Menzer, K, Devinsky, O., et al. Early manifestations of renal disease in patients with tuberous sclerosis complex. Int J Nephrol Renovasc Dis. 2017;10:91–5. http://dx.doi.org/10.2147/IJNRD.S123638
56. Wang C, Li X, Peng L, Gou X, Fan J. An update on recent developments in rupture of renal angiomyolipoma. Medicine (Baltimore). 2018;97(16):e0497. http://dx.doi.org/10.1097/ MD.0000000000010497
57. Reyna-Fabián ME, Alcántara-Ortigoza MA, Hernández-Martínez NL, Berumen J, Jiménez-García R, Gómez-Garza G, Angel Gonzalez -Del A, et al. TSC2/PKD1 contiguous gene syndrome, with emphasis on a case with an atypical mild polycystic kidney phenotype and a novel genetic variant. Nefrología. 2020;40(1):91–8. http://dx.doi.org/10.1016/j.nefro.2019.03.003
58. Rijal JP, Dhakal P, Giri S, Dahal KV. Tuberous sclerosis complex with autosomal dominant polycystic kidney disease: A rare duo. BMJ Case Rep. 2014;2014:bcr2014207471. http://dx.doi. org/10.1136/bcr-2014-207471
59. Vos N, Oyen R. Renal angiomyolipoma: The good, the bad, and the ugly. J Belg Soc Radiol. 2018;102(1):41. http://dx.doi. org/10.5334/jbsr.1536
60. Nelson CP, Sanda MG Contemporary diagnosis and management of renal angiomyolipoma. J Urol. 2002;168(4 Pt 1):1315. http://dx.doi.org/10.1016/S0022-5347(05)64440-0
61. Dickinson M, Ruckle H, Beaghler M, Hadley HR. Renal angiomyolipoma: Optimal treatment based on size and symptoms. Clin Nephrol. 1998 May;49(5):281–6.
62. Lewis EL, Palmer JM. West renal angiomyolipoma and massive retroperitoneal hemorrhage during pregnancy. J Med. 1985 Nov;143(5):675–6.
63. Petrikovsky BM, Vintzileos AM, Cassidy SB, Egan JF. Tuberous sclerosis in pregnancy. Am J Perinatol. 1990 Apr;7(2):133–5. http://dx.doi.org/10.1055/s-2007-999464
64. Raft J, Lalot JM, Meistelman C, Longrois D. Renal angiomyolipoma rupture during pregnancy, Gynecol Obstet Fertil. 2006 Oct;34(10):917–19. http://dx.doi.org/10.1016/j. gyobfe.2006.02.021
65. Schieppati A, Daina E, Sessa A, Remuzzi G, editors. Rare kid-ney diseases. Contrib Nephrol. 2001;136:33–49. http://dx.doi. org/10.1159/000060178
66. Karbowniczek M, Yu J, Henske EP. Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and non-neoplastic vascular structures. Am J Pathol. 2003;162:491–500. http://dx.doi.org/10.1016/ S0002-9440(10)63843-6
67. Lin CN, Chiang HS, Hsu SI, Huang AH, Chuang SS. Renal angiomyolipoma with a prominent angiomatous component and extramedullary hematopoiesis: A case report. Chung Hua I Hsueh Tsa Chih (Taipei). 1994;53:185–7.
68. Buj Pradilla MJ, Martí Ballesté T, Torra R, Villacampa Aubá F. Recommendations for imaging-based diagnosis and management of renal angiomyolipoma associated with tuberous sclerosis complex. Clin Kidney J. 2017 Dec 1;10(6):728–37. http://dx.doi.org/10.1093/ckj/sfx094
69. Pei Y. Diagnostic approach in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2006 Sep 1;1(5):1108– 14. http://dx.doi.org/10.2215/CJN.02190606
70. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):140–51. http://dx.doi.org/10.1056/ NEJMoa063564
71. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013 Jan 12;381(9861):125–32. http://dx.doi.org/10.1016/S0140-6736(12)61134-9
72. Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, et al. Everolimus for the treatment of lymphangioleiomyomatosis: A phase II study. Eur Respir J. 2015 Sep 1;46(3):783–94. http://dx.doi.org/10.1183/09031936.00210714
73. Martignoni G, Bonetti F, Pea M, Tardanico R, Brunelli M, Eble JN. Renal disease in adults with TSC2/PKD1 contiguous gene syndrome. Am J Surg Pathol. 2002;26(2):198–205. http:// dx.doi.org/10.1097/00000478-200202000-00006
74. Smulders YM. Large deletion causing the TSC2-PKD1 contig-uous gene syndrome without infantile polycystic disease. J Med Genet. 2003 Feb;40(2):E17. http://dx.doi.org/10.1136/jmg.40.2.e17
75. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ. ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019 Sep 10;140(11):e596–646. http://dx.doi.org/10.1161/CIR.0000000000000678
76. Kiril T, Yilmaz A, Uzer D, Dishongh KM, Quick CM, Bismar TA, et al. Renal oncocytoma revisited: A clinicopathological study of 109 cases with emphasis on problematic diagnostic features. Histopathology. 2010;57(6):893–906. http:// dx.doi.org/10.1111/j.1365-2559.2010.03726.x
77. Elsamaloty H, Abdullah A, Elzawawi M. Abdom imaging, multiple bilateral renal oncocytomas in a known case of tuberous sclerosis: A case report. Abdom Imaging. 2010 Feb;35(1):115-17. http://dx.doi.org/10.1007/s00261-008-9486-3
78. Jimenez RE, Eble JN, Reuter VE, Epstein JI, Folpe AL, de Peralta-Venturina M, et al. Concurrent angiomyolipoma and renal cell neoplasia: A study of 36 cases. Mod Pathol. 2001 Mar;14(3):157–63. http://dx.doi.org/10.1038/ modpathol.3880275
79. Samuels JA, Treatment of renal angiomyolipoma and other hamartomas in patients with tuberous sclerosis complex. CJASN. 2017 Jul;12(7):1196–202. http://dx.doi.org/10.2215/ CJN.08150816
80. Pleniceanu O, Omer D, Azaria E, Harari-Steinberg O, Dekel B. mTORC1 inhibition is an effective treatment for sporadic renal angiomyolipoma. Kidney Int Rep. 2017;3(1):155–9. http://dx. doi.org/10.1016/j.ekir.2017.07.016
81. Bissler J, Kingswood J, Radzikowska E, Zonnenberg B, Frost M, Belousova E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013;381:817–24. http://dx.doi. org/10.1016/S0140-6736(12)61767-X
82. Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, et al. Effect of everolimus on renal function in patients with tuberous sclerosis complex: Evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant. 2019;34(6):1000–8. http:// dx.doi.org/10.1093/ndt/gfy132
83. Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: A phase 2 trial. Clin Cancer Res. 2011;17:4071–81. http://dx.doi. org/10.1158/1078-0432.CCR-11-0445
84. Dabora S, Franz D, Ashwal S, Sagalowsky A, Dimario F Jr, Miles D, et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: Kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One 2011;6:e23379. http://dx.doi.org/10.1371/journal.pone.0023379
85. Cabrera-López C, Martí T, Catalá V, Torres F, Mateu S, Ballarin J. et al. Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: A two years trial. Orphanet J Rare Dis. 2012;7:87. http://dx.doi.org/10.1186/1750-1172-7-87
86. Viana SD, Reis F, Alves R. Therapeutic use of mTOR inhib-itors in renal diseases: Advances, drawbacks, and challenges. Oxid Med Cell Longev. 2018;2018:3693625. http://dx.doi. org/10.1155/2018/3693625
87. Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B, Alix S, et  al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007;67(12):5840–50. http://dx.doi.org/10.1158/0008-5472. CAN-06-4615
88. MacKeigan JP, Krueger DA. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous scle-rosis complex. Neuro Oncol. 2015;17(12):1550–9. http://dx.doi. org/10.1093/neuonc/nov152
89. Herschbein L, Liesveld JL. Dueling for dual inhibition: Means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML. Blood Rev. 2018;32(3):235–48. http://dx.doi. org/10.1016/j.blre.2017.11.006
90. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny, CJ, McWhirter C, Banaji, A. et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016;534(7606):272–6. http://dx.doi.org/10.1038/nature17963
91. Tello R, Blickman JG, Buonomo C, Herrin J. Meta analysis of the relationship between tuberous sclerosis complex and renal cell carcinoma. Eur J Radiol. 1998;27(2):131–8. http://dx.doi. org/10.1016/S0720-048X(97)00037-5