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29-11-2022 | Kidney Cancer | Educational Review

Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions

Authors: Sebastian Gallo-Bernal, Aoife Kilcoyne, Michael S. Gee, Elahna Paul

Published in: Pediatric Nephrology | Issue 10/2023

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an estimated incidence of one in 5000 to 10,000 live births worldwide. Two million people of all races and genders are estimated to have TSC secondary to mutations in one of two tumor suppressor genes, TSC1 or TSC2. The respective TSC1 and 2 gene products — hamartin and tuberin — form cytoplasmic heterodimers that inhibit mTOR-mediated cell growth and division. When mTOR inhibition is lost, people with TSC develop characteristic and usually benign tumors in various organ systems. Kidney tumors and cysts are common, particularly in the setting of TSC2 gene mutations. In most TSC patients, the number of kidney cysts is limited, their morphology is simple, their size is small, and their clinical significance is negligible. In some, cyst morphology progresses from simple to complex with the risk of malignant transformation. In others, aggressive accumulation and growth of kidney cysts can cause hypertension, impaired kidney function, and progression to kidney failure. This educational review summarizes current knowledge and remaining open questions regarding cystic kidney disease in TSC, emphasizing detection, classification, surveillance, and treatment options.

Henske EP, Jóźwiak S, Kingswood JC, Sampson JR et al (2016) Tuberous sclerosis complex. Nat Rev Dis Primers 2:16035. https://doi.org/10.1038/nrdp.2016.35CrossRefPubMed

Northrup H, Aronow ME, Bebin EM, Bissler J et al (2021) Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol 123:50–66. https://doi.org/10.1016/j.pediatrneurol.2021.07.011CrossRefPubMed

Bissler JJ, Christopher Kingswood J (2018) Renal manifestation of tuberous sclerosis complex. Am J Med Genet C Semin Med Genet 178:338–347. https://doi.org/10.1002/ajmg.c.31654CrossRefPubMed

Kingswood JC, Belousova E, Benedik MP, Carter T et al (2020) Renal manifestations of tuberous sclerosis complex: key findings from the final analysis of the TOSCA study focussing mainly on renal angiomyolipomas. Front Neurol 11:972. https://doi.org/10.3389/fneur.2020.00972CrossRefPubMedPubMedCentral

Henske EP, Cornejo KM, Wu C-L (2021) Renal cell carcinoma in tuberous sclerosis complex. Genes (Basel) 12:1585. https://doi.org/10.3390/genes12101585CrossRefPubMed

Sauter M, Belousova E, Benedik MP, Carter T et al (2021) Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increase disease awareness (TOSCA). Orphanet J Rare Dis 16:301. https://doi.org/10.1186/s13023-021-01917-yCrossRefPubMedPubMedCentral

Ewalt DH, Sheffield E, Sparagana SP, Delgado MR et al (1998) Renal lesion growth in children with tuberous sclerosis complex. J Urol 160:141–145CrossRefPubMed

Lam HC, Siroky BJ, Henske EP (2018) Renal disease in tuberous sclerosis complex: pathogenesis and therapy. Nat Rev Nephrol 14:704–716. https://doi.org/10.1038/s41581-018-0059-6CrossRefPubMed

Rakowski SK, Winterkorn EB, Paul E, Steele DJR et al (2006) Renal manifestations of tuberous sclerosis complex: incidence, prognosis, and predictive factors. Kidney Int 70:1777–1782. https://doi.org/10.1038/sj.ki.5001853CrossRefPubMed

10.

Amin S, Lux A, Calder N, Laugharne M et al (2017) Causes of mortality in individuals with tuberous sclerosis complex. Dev Med Child Neurol 59:612–617. https://doi.org/10.1111/dmcn.13352CrossRefPubMed

11.

Eijkemans MJC, van der Wal W, Reijnders LJ, Roes KCB et al (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 66:638–645. https://doi.org/10.1053/j.ajkd.2015.05.016CrossRefPubMed

12.

Shepherd CW, Gomez MR, Lie JT, Crowson CS (1991) Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66:792–796. https://doi.org/10.1016/s0025-6196(12)61196-3CrossRefPubMed

13.

Janssens P, van Hoeve K, de Waele L, de Rechter S et al (2018) Renal progression factors in young patients with tuberous sclerosis complex: a retrospective cohort study. Pediatr Nephrol 33:2085–2093. https://doi.org/10.1007/s00467-018-4003-6CrossRefPubMed

14.

Roberts PS, Chung J, Jozwiak S, Dabora SL et al (2002) SNP identification, haplotype analysis, and parental origin of mutations in TSC2. Hum Genet 111:96–101. https://doi.org/10.1007/s00439-002-0738-yCrossRefPubMed

15.

Tyburczy ME, Dies KA, Glass J, Camposano S et al (2015) Mosaic and intronic mutations in TSC1/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing. PLoS Genet 11:e1005637. https://doi.org/10.1371/journal.pgen.1005637CrossRefPubMedPubMedCentral

16.

Martin KR, Zhou W, Bowman MJ, Shih J et al (2017) The genomic landscape of tuberous sclerosis complex. Nat Commun 8:15816. https://doi.org/10.1038/ncomms15816CrossRefPubMedPubMedCentral

17.

Warncke JC, Brodie KE, Grantham EC, Catarinicchia SP et al (2017) Pediatric renal angiomyolipomas in tuberous sclerosis complex. J Urol 197:500–506. https://doi.org/10.1016/j.juro.2016.09.082CrossRefPubMed

18.

Dabora SL, Jozwiak S, Franz DN, Roberts PS et al (2001) 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 68:64–80. https://doi.org/10.1086/316951CrossRefPubMed

19.

Francis J, DiMario FJ Jr. (2019) NORD’s rare disease database: tuberous sclerosis. https://rarediseases.org/rare-diseases/tuberous-sclerosis/. Accessed 28 October 2022.

20.

Yang H, Yu Z, Chen X, Li J et al (2021) Structural insights into TSC complex assembly and GAP activity on Rheb. Nat Commun 12:339. https://doi.org/10.1038/s41467-020-20522-4CrossRefPubMedPubMedCentral

21.

Pema M, Drusian L, Chiaravalli M, Castelli M et al (2016) mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nat Commun 7:10786. https://doi.org/10.1038/ncomms10786CrossRefPubMedPubMedCentral

22.

Siroky BJ, Towbin AJ, Trout AT, Schäfer H et al (2017) Improvement in renal cystic disease of tuberous sclerosis complex after treatment with mammalian target of rapamycin inhibitor. J Pediatr 187:318-322.e2. https://doi.org/10.1016/j.jpeds.2017.05.015CrossRefPubMed

23.

Low SH, Vasanth S, Larson CH, Mukherjee S et al (2006) Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell 10:57–69. https://doi.org/10.1016/j.devcel.2005.12.005CrossRefPubMed

24.

Lai Y, Jiang Y (2020) Reciprocal regulation between primary cilia and mTORC1. Genes (Basel) 11:711. https://doi.org/10.3390/genes11060711CrossRefPubMed

25.

Shillingford JM, Murcia NS, Larson CH, Low SH et al (2006) The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A 103:5466–5471. https://doi.org/10.1073/pnas.0509694103CrossRefPubMedPubMedCentral

26.

Yamamoto Y, Mizushima N (2021) Autophagy and ciliogenesis. JMA J 4:207–215. https://doi.org/10.31662/jmaj.2021-0090

27.

Hartman TR, Liu D, Zilfou JT, Robb V et al (2009) The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum Mol Genet 18:151–163. https://doi.org/10.1093/hmg/ddn325CrossRefPubMed

28.

Bonsib SM, Boils C, Gokden N, Grignon D et al (2016) Tuberous sclerosis complex: hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms. Pathol Res Pract 212:972–979. https://doi.org/10.1016/j.prp.2016.04.005CrossRefPubMed

29.

Bissler JJ, Zadjali F, Bridges D, Astrinidis A et al (2019) Tuberous sclerosis complex exhibits a new renal cystogenic mechanism. Physiol Rep 7:e13983. https://doi.org/10.14814/phy2.13983

30.

Kumar P, Zadjali F, Yao Y, Johnson D et al (2022) Tsc2 mutation induces renal tubular cell nonautonomous disease. Genes Dis 9:187–200. https://doi.org/10.1016/j.gendis.2021.03.010CrossRefPubMed

31.

Ståhl A-L, Johansson K, Mossberg M, Kahn R et al (2019) Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases. Pediatr Nephrol 34:11–30. https://doi.org/10.1007/s00467-017-3816-zCrossRefPubMed

32.

Pomatto MAC, Gai C, Bussolati B, Camussi G (2017) Extracellular vesicles in renal pathophysiology. Front Mol Biosci 4:37. https://doi.org/10.3389/fmolb.2017.00037CrossRefPubMedPubMedCentral

33.

Yates JR, MacLean C, Higgins JNP, Humphrey A et al (2011) The Tuberous Sclerosis 2000 study: presentation, initial assessments and implications for diagnosis and management. Arch Dis Child 96:1020–1025. https://doi.org/10.1136/adc.2011.211995CrossRefPubMed

34.

Consugar MB, Wong WC, Lundquist PA, Rossetti S et al (2008) Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int 74:1468–1479. https://doi.org/10.1038/ki.2008.485CrossRefPubMedPubMedCentral

35.

Sampson JR, Maheshwar MM, Aspinwall R, Thompson P et al (1997) Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet 61:843–851. https://doi.org/10.1086/514888CrossRefPubMedPubMedCentral

36.

Hindman N, Ngo L, Genega EM, Melamed J et al (2012) Angiomyolipoma with minimal fat: can it be differentiated from clear cell renal cell carcinoma by using standard MR techniques? Radiology 265:468–477. https://doi.org/10.1148/radiol.12112087CrossRefPubMedPubMedCentral

37.

Park BK (2017) Renal angiomyolipoma: radiologic classification and imaging features according to the amount of fat. AJR Am J Roentgenol 209:826–835. https://doi.org/10.2214/AJR.17.17973CrossRef

38.

Wang MX, Segaran N, Bhalla S, Pickhardt PJ et al (2021) Tuberous sclerosis: current update. Radiographics 41:1992–2010. https://doi.org/10.1148/rg.2021210103CrossRefPubMed

39.

Yamakado K, Tanaka N, Nakagawa T, Kobayashi S et al (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225:78–82. https://doi.org/10.1148/radiol.2251011477CrossRefPubMed

40.

Trnka P, Kennedy SE (2021) Renal tumors in tuberous sclerosis complex. Pediatr Nephrol 36:1427–1438. https://doi.org/10.1007/s00467-020-04775-1CrossRefPubMed

41.

Robert A, Leroy V, Riquet A, Gogneaux L et al (2016) Renal involvement in tuberous sclerosis complex with emphasis on cystic lesions. Radiol Med 121:402–408. https://doi.org/10.1007/s11547-015-0572-7CrossRefPubMed

42.

Casper KA, Donnelly LF, Chen B, Bissler JJ (2002) Tuberous sclerosis complex: renal imaging findings. Radiology 225:451–456. https://doi.org/10.1148/radiol.2252011584CrossRefPubMed

43.

Gimpel C, Avni EF, Breysem L, Burgmaier K et al (2019) Imaging of kidney cysts and cystic kidney diseases in children: an international working group consensus statement. Radiology 290:769–782. https://doi.org/10.1148/radiol.2018181243CrossRefPubMed

44.

Bernstein J (1993) Glomerulocystic kidney disease – nosological considerations. Pediatr Nephrol 7:464–470. https://doi.org/10.1007/BF00857576CrossRefPubMed

45.

Wilson MP, Patel D, Murad MH, McInnes MDF et al (2020) Diagnostic performance of MRI in the detection of renal lipid-poor angiomyolipomas: a systematic review and meta-analysis. Radiology 296:511–520. https://doi.org/10.1148/radiol.2020192070CrossRefPubMed

46.

Chan JP, Back SJ, Vatsky S, Calle-Toro JS et al (2021) Utility of contrast-enhanced ultrasound for solid mass surveillance and characterization in children with tuberous sclerosis complex: an initial experience. Pediatr Nephrol 36:1775–1784. https://doi.org/10.1007/s00467-020-04835-6CrossRefPubMed

47.

Raab C, Gilligan LA, Trout AT, Krueger DA et al (2020) mTOR inhibitor therapy for tuberous sclerosis complex: longitudinal study of muscle mass determined by abdominal cross-sectional imaging with CT and MRI. Radiol Imaging Cancer 2:e190091. https://doi.org/10.1148/rycan.2020190091CrossRefPubMedPubMedCentral

48.

Sasongko TH, Ismail NFD, Zabidi-Hussin Z (2016) Rapamycin and rapalogs for tuberous sclerosis complex. Cochrane Database Syst Rev 7:CD011272. https://doi.org/10.1002/14651858.CD011272.pub2

49.

Lin C-H, Chao C-T, Wu M-Y, Lo W-C et al (2019) Use of mammalian target of rapamycin inhibitors in patient with autosomal dominant polycystic kidney disease: an updated meta-analysis. Int Urol Nephrol 51:2015–2025. https://doi.org/10.1007/s11255-019-02292-1CrossRefPubMed

50.

Walz G, Budde K, Mannaa M, Nürnberger J et al (2010) Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 363:830–840. https://doi.org/10.1056/NEJMoa1003491CrossRefPubMed

51.

Serra AL, Poster D, Kistler AD, Krauer F et al (2010) Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 363:820–829. https://doi.org/10.1056/NEJMoa0907419CrossRefPubMed

52.

Yang P, Cornejo KM, Sadow PM, Cheng L et al (2014) Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol 38:895–909. https://doi.org/10.1097/PAS.0000000000000237CrossRefPubMedPubMedCentral

53.

Peron A, Vignoli A, la Briola F, Volpi A et al (2016) Do patients with tuberous sclerosis complex have an increased risk for malignancies? Am J Med Genet A 170:1538–1544. https://doi.org/10.1002/ajmg.a.37644CrossRefPubMed

54.

Bernstein J, Robbins TO (1991) Renal involvement in tuberous sclerosis. Ann N Y Acad Sci 615:36–49. https://doi.org/10.1111/j.1749-6632.1991.tb37746.xCrossRefPubMed

55.

Downey RT, Dillman JR, Ladino-Torres MF, McHugh JB et al (2012) CT and MRI appearances and radiologic staging of pediatric renal cell carcinoma. Pediatr Radiol 42:410–417. https://doi.org/10.1007/s00247-011-2319-5CrossRefPubMed

56.

Chung EM, Lattin GE, Fagen KE, Kim AM et al (2017) Renal tumors of childhood: radiologic-pathologic correlation part 2. The 2nd decade: from the radiologic pathology archives. Radiographics 37:1538–1558. https://doi.org/10.1148/rg.2017160189CrossRefPubMed

57.

Saltzman AF, Carrasco A, Colvin AN, Meyers ML et al (2018) Can a modified Bosniak classification system risk stratify pediatric cystic renal masses? J Urol 200:434–439. https://doi.org/10.1016/j.juro.2018.03.076CrossRefPubMed

58.

Bosniak MA (1986) The current radiological approach to renal cysts. Radiology 158:1–10. https://doi.org/10.1148/radiology.158.1.3510019CrossRefPubMed

59.

Silverman SG, Pedrosa I, Ellis JH, Hindman NM et al (2019) Bosniak classification of cystic renal masses, version 2019: an update proposal and needs assessment. Radiology 292:475–488. https://doi.org/10.1148/radiol.2019182646CrossRefPubMed

60.

Tse JR, Shen J, Shen L, Yoon L et al (2021) Bosniak classification of cystic renal masses version 2019: comparison of categorization using CT and MRI. AJR Am J Roentgenol 216:412–420. https://doi.org/10.2214/AJR.20.23656CrossRef

61.

Sanchez A, Feldman AS, Hakimi AA (2018) Current management of small renal masses, including patient selection, renal tumor biopsy, active surveillance, and thermal ablation. J Clin Oncol 36:3591–3600. https://doi.org/10.1200/JCO.2018.79.2341CrossRefPubMedPubMedCentral

62.

Kozlowski P, Roberts P, Dabora S, Franz D et al (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 121:389–400. https://doi.org/10.1007/s00439-006-0308-9CrossRefPubMed

63.

Brook-Carter PT, Peral B, Ward CJ, Thompson P et al (1994) Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – a contiguous gene syndrome. Nat Genet 8:328–332. https://doi.org/10.1038/ng1294-328CrossRefPubMed

64.

Shang S, Mei Y, Wang T, Zheng X et al (2022) Diagnosis and genotype-phenotype correlation in patients with PKD1/TSC2 contiguous gene deletion syndrome. Clin Nephrol 97:328–338. https://doi.org/10.5414/CN110476CrossRefPubMed

65.

Back SJ, Andronikou S, Kilborn T, Kaplan BS et al (2015) Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome. Pediatr Radiol 45:386–395. https://doi.org/10.1007/s00247-014-3147-1CrossRefPubMed

66.

Gimpel C, Bergmann C, Bockenhauer D, Breysem L et al (2019) International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol 15:713–726. https://doi.org/10.1038/s41581-019-0155-2CrossRefPubMedPubMedCentral

Title: Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions
Authors: Sebastian Gallo-Bernal
Aoife Kilcoyne
Michael S. Gee
Elahna Paul
Publication date: 29-11-2022
Publisher: Springer Berlin Heidelberg
Keywords: Kidney Cancer
Kidney Cancer
Tuberous Sclerosis
Kidney Cancer
Cystic Kidney Disease
Published in: Pediatric Nephrology / Issue 10/2023
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-022-05820-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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