Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Pediatric Nephrology
Published in: Pediatric Nephrology 7/2017

01-07-2017 | Educational Review

Treatment of renal angiomyolipoma in tuberous sclerosis complex (TSC) patients

Authors: S. Brakemeier, F. Bachmann, K. Budde

Published in: Pediatric Nephrology | Issue 7/2017

Login to get access

Abstract

In adult tuberous sclerosis complex (TSC) patients, renal complications are the leading cause of death. Beginning in childhood, up to 80 % of patients develop renal angiomyolipoma characterized by a size-dependent risk of life-threatening bleeding. After discovery of the two causative genes, TSC1 and TSC2, and the role of mammalian target of rapamycin (mTOR) regulation in the pathogenesis of TSC, an increasing number of clinical studies evaluating mTOR inhibition in TSC patients have shown impressive results in many organ manifestations, such as brain, lung, and kidney. For renal angiomyolipoma, mTOR inhibitor treatment fundamentally changed the approach from preventive embolization or even partial nephrectomy to everolimus treatment in order to preserve kidney function.
Literature
1.
Budde K, Gaedeke J (2012) Tuberous sclerosis complex–associated angiomyolipomas: focus on mTOR inhibition. Am J Kidney Dis 59:276–283CrossRefPubMed
2.
Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355:1345–1356CrossRefPubMed
3.
Jozwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J (2000) Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol 15:652–659CrossRefPubMed
4.
Northrup H, Krueger DA (2013) Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:243–254CrossRefPubMedPubMedCentral
5.
Krueger DA, Northrup H (2013) Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:255–265CrossRefPubMedPubMedCentral
6.
7.
8.
Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225:78–82
9.
Eijkemans MJ, van der Wal W, Reijnders LJ, Roes KC, van Waalwijk van Doorn-Khosrovani SB, Pelletier C, Magestro M, Zonnenberg B (2015) 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 66:638–645CrossRefPubMed
10.
Dixon BP, Hulbert JC, Bissler JJ (2011) Tuberous sclerosis complex renal disease. Nephron Exp Nephrol 118:e15–e20CrossRefPubMed
11.
Bissler J, Cappell K, Charles H, Song X, Liu Z, Prestifilippo J, Hulbert J (2015) Rates of interventional procedures in patients with tuberous sclerosis complex-related renal angiomyolipoma. Curr Med Res Opin 31:1501–1507CrossRefPubMed
12.
Shepherd CW, Gomez MR, Lie JT, Crowson CS (1991) Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66:792–796CrossRefPubMed
13.
O’Callaghan FJ, Noakes MJ, Martyn CN, Osborne JP (2004) An epidemiological study of renal pathology in tuberous sclerosis complex. BJU Int 94:853–857CrossRefPubMed
14.
Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, Nellist M, Gamble V, Harris PC, Sampson JR (1994) Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease–a contiguous gene syndrome. Nat Genet 8:328–332
15.
16.
Kozlowski P, Roberts P, Dabora S, Franz D, Bissler J, Northrup H, Au KS, Lazarus R, Domanska-Pakiela D, Kotulska K, Jozwiak S, Kwiatkowski DJ (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 121(3–4):389–400
17.
Back SJ, Andronikou S, Kilborn T, Kaplan BS, Darge K (2015) Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome. Pediatr Radiol 45:386–395CrossRefPubMed
18.
Consugar MB, Wong WC, Lundquist PA, Rossetti S, Kubly VJ, Walker DL, Rangel LI, Aspinwall R, Niaudet WP, Ozen S, David A, Velinov M, Bergstralh EJ, Bae KT, Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Sampson JR, Dawson BD, Harris PC; CRISP Consortium (2008) Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int 74:1468–1479
19.
Clarke A, Hancock E, Kingswood C, Osborne JP (1999) End-stage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transplant 14:988–991CrossRefPubMed
20.
Vekeman F, Magestro M, Karner P, Duh MS, Nichols T, van Waalwijk van Doorn-Khosrovani Barjesteh S, Zonnenberg BA (2015) Kidney involvement in tuberous sclerosis complex: the impact on healthcare resource use and costs. J Med Econ 18:1060–1070CrossRefPubMed
21.
Huang J, Dibble CC, Matsuzaki M, Manning BD (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28:4104–4115CrossRefPubMedPubMedCentral
22.
Dixon BP, Kingswood JC, Bissler JJ (2015) Tuberous sclerosis complex renal disease. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, Himmelfarb J, Remuzzi G (eds) Oxford textbook of clinical nephrology, 4th edn. Oxford University Press, Oxford, pp 2732–2738CrossRef
23.
24.
McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group (2011) Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 364:1595–1606
25.
Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, Watson PC, Howe CJ, Doyle T, Pointon K, Cross JJ, Tattersfield AE, Kingswood JC, Sampson JR (2011) Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res 17:4071–4081CrossRefPubMed
26.
Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J (2011) Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med 154:797–805, W-292-3CrossRefPubMedPubMedCentral
27.
Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S (2013) 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 381:125–132CrossRefPubMed
28.
Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801–1811CrossRefPubMed
29.
Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K (2013) Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381:817–824CrossRefPubMed
30.
Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Berkowitz N, Miao S, Segal S, Peyrard S, Budde K (2016) Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant 31:111–119CrossRefPubMed
31.
Nathan N, Wang JA, Li S, Cowen EW, Haughey M, Moss J, Darling TN (2015) Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. J Am Acad Dermatol 73:802–808CrossRefPubMedPubMedCentral
32.
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358:140–151CrossRefPubMedPubMedCentral
33.
Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack FX (2001) Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 164:661e8
34.
Pirson Y (2013) Tuberous sclerosis complex-associated kidney angiomyolipoma: from contemplation to action. Nephrol Dial Transplant 28:1680–1685CrossRefPubMed
35.
Tyburczy ME, Jozwiak S, Malinowska IA, Chekaluk Y, Pugh TJ, Wu CL, Nussbaum RL, Seepo S, Dzik T, Kotulska K, Kwiatkowski DJ (2014) A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex. Hum Mol Genet 24:1836–1842CrossRefPubMedPubMedCentral
36.
Guo J, Tretiakova MS, Troxell ML, Osunkoya AO, Fadare O, Sangoi AR, Shen SS, Lopez-Beltran A, Mehra R, Heider A, Higgins JP, Harik LR, Leroy X, Gill AJ, Trpkov K, Campbell SC, Przybycin C, Magi-Galluzzi C, McKenney JK (2014) Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am J Surg Pathol 38:1457–1467CrossRefPubMed
37.
Cabrera-López C, Bullich G, Martí T, Català V, Ballarín J, Bissler JJ, Harris PC, Ars E, Torra R (2015) Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated. BMC Med Genet 16:39CrossRefPubMedPubMedCentral
38.
Aguiar PV, Campistol JM, Diekmann F (2015) Safety of mTOR inhibitors in adult solid organ transplantation. Expert Opin Drug Saf
39.
Moschetta M, Reale A, Marasco C, Vacca A, Carratù MR (2014) Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations. Br J Pharmacol 171:3801–3813CrossRefPubMedPubMedCentral
40.
Budde K, Zonnenberg BA, Frost M, Cheung W, Urva S, Brechenmacher T, Stein K, Chen D, Kingswood C, Bissler JJ (2015) Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis. Br J Clin Pharm 81:958–970
41.
Kotulska K, Borkowska J, Jozwiak S (2013) Possible prevention of tuberous sclerosis complex lesions. Pediatrics 132:e239–e242CrossRefPubMed
42.
Wiegand G, May TW, Ostertag P, Boor R, Stephani U, Franz DN (2013) Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol 17:631–638CrossRefPubMed
43.
Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA (2014) Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr 164:1195–1200CrossRefPubMed
44.
Curatolo P (2015) Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol 52:281–289CrossRefPubMed
45.
Sadowski K, Kotulska-Jóźwiak K, Jóźwiak S (2015) Role of mTOR inhibitors in epilepsy treatment. Pharmacol Rep 67:636–646CrossRefPubMed
46.
Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN (2013) Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 74:679–687CrossRefPubMed
47.
Duerr M, Glander P, Diekmann F, Dragun D, Neumayer HH, Budde K (2010) Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol 5:703–708CrossRefPubMedPubMedCentral
48.
Kingswood JC, Bruzzi P, Curatolo P, de Vries PJ, Fladrowski C, Hertzberg C, Jansen AC, Jozwiak S, Nabbout R, Sauter M, Touraine R, O’Callaghan F, Zonnenberg B, Crippa S, Comis S, d’Augères GB, Belousova E, Carter T, Cottin V, Dahlin M, Ferreira JC, Macaya A, Benedik MP, Sander V, Youroukos S, Castellana R, Ulker B, Feucht M (2014) TOSCA - first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. Orphanet J Rare Dis 9:182CrossRefPubMedPubMedCentral
49.
Tran LH, Zupanc ML (2015) Long-term everolimus treatment in individuals with tuberous sclerosis complex: a review of the current literature. Pediatr Neurol 53:23–30CrossRefPubMed
50.
Somers MJ, Paul E (2015) Safety considerations of mammalian target of rapamycin inhibitors in tuberous sclerosis complex and renal transplantation. J Clin Pharmacol 55:368–376CrossRefPubMed
51.
Kingswood C, Bolton P, Crawford P, Harland C, Johnson SR, Sampson JR, Shepherd C, Spink J, Demuth D, Lucchese L, Nasuti P, Gray E, Pinnegar A, Magestro M (2015) 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 Neurol
52.
Fritsche L, Budde K, Dragun D, Einecke G, Diekmann F, Neumayer HH (2004) Testosterone concentrations and sirolimus in male renal transplant patients. Am J Transplant 4:130–131CrossRefPubMed
53.
Braun M, Young J, Reiner CS, Poster D, Krauer F, Kistler AD, Kristanto P, Wang X, Liu Y, Loffing J, Andreisek G, von Eckardstein A, Senn O, Wüthrich RP, Serra AL (2012) Low-dose oral sirolimus and the risk of menstrual-cycle disturbances and ovarian cysts: analysis of the randomized controlled SUISSE ADPKD trial. PLoS One 7, e45868CrossRefPubMedPubMedCentral
54.
Pape L, Ahlenstiel T (2014) mTOR inhibitors in pediatric kidney transplantation. Pediatr Nephrol 29:1119–1129CrossRefPubMed
55.
Ganschow R, Pape L, Sturm E, Bauer J, Melter M, Gerner P, Höcker B, Ahlenstiel T, Kemper M, Brinkert F, Sachse MM, Tönshoff B (2013) Growing experience with mTOR inhibitors in pediatric solid organ transplantation. Pediatr Transplant 17:694–706PubMed
56.
Kranz B, Wingen AM, Vester U, Konig J, Hoyer PF (2013) Long-term side effects of treatment with mTOR inhibitors in children after renal transplantation. Pediatr Nephrol 28:1293–1298CrossRefPubMed
57.
De Waele L, Lagae L, Mekahli D (2015) Tuberous sclerosis complex: the past and the future. Pediatr Nephrol 30:1771–1780CrossRefPubMed
58.
Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Berkowitz N, Anak O, Niolat J, Jozwiak S (2014) Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 15:1513–1520CrossRefPubMed
59.
Franz DN, Agricola K, Mays M, Tudor C, Care MM, Holland-Bouley K, Berkowitz N, Miao S, Peyrard S, Krueger DA (2015) Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol
60.
Kotulska K, Chmielewski D, Borkowska J, Jurkiewicz E, Kuczyński D, Kmieć T, Łojszczyk B, Dunin-Wąsowicz D, Jóźwiak S (2013) Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neurol 17:479–485CrossRefPubMed
61.
Kingswood JC, Jozwiak S, Belousova ED, Frost MD, Kuperman RA, Bebin EM, Korf BR, Flamini JR, Kohrman MH, Sparagana SP, Wu JY, Brechenmacher T, Stein K, Berkowitz N, Bissler JJ, Franz DN (2014) The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1. Nephrol Dial Transplant 29:1203–1210CrossRefPubMedPubMedCentral
62.
Curatolo P, Moavero R, de Vries PJ (2015) Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 14:733–745CrossRefPubMed
63.
Leclezio L, de Vries PJ (2015) Advances in the treatment of tuberous sclerosis complex. Curr Opin Psychiatr 28:113–120
64.
Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W (2015) Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anticancer Drugs 26:437–442CrossRefPubMed
65.
Ferraresso M, Belingheri M, Ginevri F, Murer L, Dello Strologo L, Cardillo M, Parodi A, Ghirardo G, Guzzo I, Innocente A, Ghio L (2014) Three-year safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. Pediatr Transplant 18:350–356CrossRefPubMed
Metadata
Title
Treatment of renal angiomyolipoma in tuberous sclerosis complex (TSC) patients
Authors
S. Brakemeier
F. Bachmann
K. Budde
Publication date
01-07-2017
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 7/2017
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-016-3474-6

Other articles of this Issue 7/2017

Pediatric Nephrology 7/2017 Go to the issue

Original Article

Association among prematurity (<30 weeks’ gestational age), blood pressure, urinary albumin, calcium, and phosphate in early childhood

Clinical Quiz

An atypical case of a 2-year-old boy with acute kidney injury: a race against time. Answers

Editorial

C4d deposits in IgA nephropathy: where does complement activation come from?

Original Article

Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy

Letter to the Editor

Children with Henoch–Schönlein purpura with low complement levels: follow-up for >6 years

Brief Report

Challenges in establishing genotype–phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations