Enhancing Disease Awareness for Tuberous Sclerosis Complex in Patients with Radiologic Diagnosis of Renal Angiomyolipoma: An Observational Study

Enhancing Disease Awareness for Tuberous Sclerosis Complex in Patients with Radiologic Diagnosis of Renal Angiomyolipoma: An Observational Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Enhancing Disease Awareness for Tuberous Sclerosis Complex in Patients with Radiologic Diagnosis of Renal Angiomyolipoma: An Observational Study Kathrin Bausch, Christian Wetterauer, Julian Diethelm, Jan Ebbing, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-103693/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jan, 2021 Read the published version in BMC Nephrology → Version 1 posted 8 You are reading this latest preprint version Abstract Background Tuberous Sclerosis Complex (TSC) is a genetic disorder, with renal manifestations like angiomyolipoma (AML) occurring in 70-80% of patients. AML usually cause more complications in TCS patients than in non-TSC patients. However, AML patients are not routinely investigated for TSC. Our aim was to retrospectively assess the correlation between radiologically diagnosed AML and TSC. Methods All patients were stratified into AML related vs. unrelated to TSC. Correlations were calculated to determine the association between age, AML, and TSC. Results Complete data were available for 521 patients with renal AML, in 7 of which the concurrent diagnosis of TSC was found. Younger age significantly positively correlated with the prevalence of TSC in AML patients (p<0.01). 37 (7%) of the 521 patients were within the age-range of 18-40 years, in which TSC occurred in 6 cases, 4 (66.7%) of which presented with multiple, bilateral renal AML (p<0.05), and 2 (33.3%) of which with a single, unilateral AML (p<0.05). In patients with AML but without TSC, unilateral AML was found in 83.9% and bilateral AML in 16.1% (p<0.05). Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95% CI 3.2–344.0; p=0.003) (but not unilateral AML (OR 0.09; 95% CI 0.01–0.88; p=0.04)) to be a risk factor for TSC. Conclusions The presence of bilateral AML in patients within the age-range of 18-40 years should raise suspicion for TSC as the underlying cause. Therefore, our advice is to refer patients with multiple bilateral renal AML for further investigations regarding TSC. Urology & Nephrology angiomyolipoma chronic kidney disease renal angiomyolipoma tuberous sclerosis Tuberous Sclerosis Complex Figures Figure 1 Background Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder with a birth incidence of 1:6,000 and an estimated 1 million affected individuals worldwide ( 1 ). TSC is caused by an inactivating mutation in either the TSC-1 or the TSC-2 gene, which code for the proteins hamartin and tuberin ( 2 ). These proteins form a complex that activates the GTPase-activating protein Rheb to inhibit the mechanistic Target of Rapamycin (mTOR). The lack of mTOR-inactivation leads to an increase of protein synthesis, cellular metabolism, differentiation, and growth ( 3 ), which may affect virtually every organ. Therefore, TSC is very variable in its clinical manifestations ( 4 ). Formerly, TSC was defined by Vogt’s triad of facial angiofibromas, mental retardation, and intractable epilepsy ( 5 ). Nowadays, the clinical diagnosis is usually confirmed by either a set of major and minor diagnostic criteria or by the identification of a heterozygous pathogenic variant in TSC-1 or TSC-2 by molecular genetic testing ( 6 ). Even though neurological (90%) and cutaneous (90%) manifestations, such as cortical tubers, epilepsy, giant cell astrocytoma, hydrocephalus, neurodevelopmental impairment, and facial angiofibromas ( 4 ), are the most common symptoms of TSC, 70 to 80% of TSC patients are also affected by renal angiomyolipoma (AML). Histologically, these benign tumours are composed of blood vessels, adipose tissue, and smooth muscle ( 7 ). In contrast to sporadic AML, TSC-associated AML usually manifest in childhood and adolescence ( 4 , 8 ). Growing renal AML pose a significant cause of mortality in TSC patients, since they bear the risk of severe life-threatening haemorrhage ( 9 ) and impair the renal parenchyma, which leads to chronic kidney disease (CKD) and eventually end-stage renal disease. Given the current world population, the incidence of TSC, and the frequency of renal involvement, approximately 500,000 patients with TSC worldwide have at least CKD stage 1 ( 10 ). A literature review supports the impression that AML in patients with TSC tends to present earlier, with larger tumours of greater multiplicity, and more frequently in combination with haemorrhage, than in sporadic-type AML patients ( 11 ). In general, surgical resection is avoided whenever possible in order to preserve renal function; interventions are required in case of persistent pain or acute or repeated bleeding episodes. The risk of bleeding increases with the size of AML. Therefore, beyond therapeutic nephron-sparing surgery or embolization, prophylactic intervention in large AML are recommended ( 12 ). In TSC patients, new targeted treatment options with mTOR-inhibitors proved to be beneficial – especially in AML patients ( 13 ). AML are mostly diagnosed by computed tomography (CT), magnetic resonance imaging (MRI), or sonography ( 14 ), generally with near certainty due to their unique appearance. An imaging study involving 12,970 male and 4,971 female Japanese healthy adults identified renal AML in 13 (0.1%) males and 11 (0.22%) females ( 15 ). However, even though the correlation between AML and TSC has been described and TSC patients have an increased risk for AML-related complications, disease awareness for TSC in AML patients is low in clinical practice. Therefore, the aim of this study was to investigate whether the radiologic diagnosis of renal AML can lead to the identification of TSC patients and thus increase disease awareness for TSC. Methods Study Design and Setting We performed an observational study at the departments of Urology and Radiology of the University Hospital Basel – a tertiary care centre in Switzerland. We retrospectively analysed all CT, MRI, and sonography reports performed between 2010 and 2016. The study protocol was approved by the Ethics Committee of Northwestern and Central Switzerland, with a waiver for individual informed consent (No. 2018-00037). We followed the ‘Strengthening the Reporting of Observational Studies in Epidemiology’ guidelines. Patient Selection Between January 2010 and December 2016, all CT, MRI, and sonography reports provided by the radiological reporting system were screened using the search terms “AML” and “angiomyolipoma”, in order to identify patients suffering from AML. The occurrence of renal AML was confirmed by manually reviewing the radiologic reports. In case of repeated exams, the exam with the first diagnosis was chosen for analysis. Only patients with completed datasets and patients aged 18 years and older were included. Data Collection and Definitions We extracted all relevant information from in-house electronic medical records. The medical history was reviewed and patients with concurrent TSC (TSC+) were identified by clinical diagnosis in the medical history, independent of the method of initial testing for TSC (e.g. genetic testing, clinical presentation). Statistical Analysis Correlations were calculated using a non-normality Spearman’s rank correlation coefficient to determine the association between age, AML, and TSC. Correlation of nominal parameters (age group, AML, and TSC) were calculated using the phi-coefficient. All tests were performed at a significance level of α = 0.05. Continuous data are shown as median with interquartile range (IQR). All analyses were performed with SPSS Statistics 19 (SPSS Inc., Chicago, Illinois, USA) and Graph Pad Prism Version 6.0 (GraphPad Software, La Jolla, California, USA). Results The search terms were identified in 1,122 (1.06%) of the overall 105,694 radiological reports, and the manual review of these reports led to the identification of 599 (53.4%) patients. Complete data were available for 547 (91.3%) of these patients, in 521 (95.2%; 357 (68.5%) females and 164 (31.5%) males) of which renal AML was present (AML+). The concurrent diagnosis of TSC was confirmed in 7 (1.3%) of these 521 patients (3 (0.6%) females and 4 (0.8%) males; Fig. 1 ). Median (IQR) AML + patients’ age was 67.5 (19–84) years, and median (IQR) AML+/TSC + patients’ age was 28.3 (19–42) years. AML diagnosis was primarily confirmed by CT (295; 56.6%), followed by sonography (172; 33.0%) and MRI (54; 10.4%) (Table 1 ). Table 1. Patient Characteristics. AML+, angiomyolipoma positive; CT, computed tomography; MRI, magnetic resonance imaging; TSC+, tuberous sclerosis complex positive. Among all age groups, we found no significant correlation between presence of AML and concurrent TSC diagnosis (r = 0.03; p > 0.553). Younger age, however, significantly correlated with of the occurrence of TSC (p < 0.01). 37 (7.1%) of the 521 AML + patients had an age range of 18–40 years, 15 (2.9%) had an age range of 40–45 years, and 475 (91.2%) were older than 45 years (Table 1 ). Prevalences of TSC in these age range-groups were 16.2% (6/37), 6.7% (1/15), and 0% (0/475), respectively. 4 (66.7%) and 2 (33.3%) of the 6 patients with an age range of 18–40 years presented with bilateral and unilateral renal AML, respectively (p < 0.05). The TSC + patient with an age range of 40–45 years also showed multiple bilateral AML. TSC + patients with bilateral renal AML had multiple AML lesions, whereas all TSC + patients with unilateral AML had only a single lesion. In AML+/TSC- patients, unilateral and bilateral AML was found in 83.9% (26/31) and 16.1% (5/31; p < 0.05), respectively. Among the TSC- group, unilateral AML presented predominantly (92.3%; 24/26) and bilateral AML uniquely (100%; 5/5) as a single lesion (Table 2 ). Table 2 Angiomyolipoma and tuberous sclerosis complex in the age group 18 to 40 years. AML+ TSC- TSC+ p-values unilateral bilateral total 28 9 37 83.9% (26/31) 16.1% (5/31) 31 33.3% (2/6) 66.7% (4/6) 6 < 0.05 < 0.05 < 0.05 AML+, angiomyolipoma positive; TSC+/-, tuberous sclerosis positive/negative. The presence of renal AML, either uni- or bilateral, significantly correlated with a concurrent TSC diagnosis (p = 0.028). Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95%CI 3.2–344.0; p = 0.003) (but not unilateral AML (OR 0.09; 95%CI 0.01–0.88; p = 0.04)) to be a risk factor for the presence of TSC. Discussion In our study, we identified an overall TSC prevalence in AML + patients of 1.3%. Two thirds of the AML + patients were female and one third male (68.5% vs 31.5%). Accordingly, 0.6% of the male and 0.8% of the female AML + patients had concurrent TSC. These findings are in line with the literature: while the prevalence of TSC was similar in female and male patients, the clinical manifestation – i.e., the prevalence of AML – differed between genders. The higher prevalence of AML in females has been reported previously ( 8 ). Sporadic AML is known to exhibit predominance in female patients as an effect of growth stimulation of oestrogen and progesterone receptors in AML ( 1 ). We found a significant positive correlation between younger age and TSC prevalence in AML + patients. Epidemiological studies regarding TSC patients show an increase of renal AML manifestation during childhood and adolescence ( 4 ). In our study, 37 AML + patients were within the age range of 18–40 years, and the prevalence of TSC in this group was 16.2%. Those findings are in line with the results of prior studies, where 1% of all AML patients had concurrent TCS, but 10% of the AML patients with an age range of 18–40 years ( 1 ). A previous longitudinal study demonstrated that 55% of paediatric TSC patients with a mean age of 6.9 years had some type of renal abnormality, and that this proportion even rose to 80% at a mean age of 10.5 years ( 15 ). Renal AML was by far the most common form of involvement. The authors concluded that in TSC, renal involvement begins in infancy and increases with age. Studies have also demonstrated that the incidence of AML in patients with TSC increased with age and that rapid growth occurred in childhood and adolescence, with slower growth into adulthood ( 16 ). Consequently, we expect that if patients < 18 years would have been included in our study, more cases of TSC would have been identified. In our cohort, 66.7% of the TCS patients with an age range of 18–40 year presented with bilateral renal AML and 33.3% with unilateral renal AML (p < 0.05). Multiple lesions were identified in all TSC + patients with bilateral AML, whereas primarily single lesions were found in both uni- and bilateral AML+/TSC- patients. The distribution of uni- and bilateral AML in TSC patients has already been investigated in the 1980s: 29% of the AML were unilateral, and 71% occurred on both sides ( 16 ). Our findings are also in line with previous findings that demonstrated more bilateral AML and a higher multiplicity in AML patients with TSC than in AML patients without TSC ( 11 ). In our study, the majority of AML (91.2%) was identified in patients under the age of 45 years. A previously published study investigating the AML incidence in TSC patients demonstrated a significant association between increasing age and the incidence of AML ( 8 ). However, in our cohort, no patient above the age of 45 years had been diagnosed with TSC. These findings may indicate that TSC patients are underdiagnosed due to the formerly limited awareness for TSC and lost to follow-up. Furthermore, life expectancy of most TSC patients is limited to young adulthood due to malignancies and unexpected death in epilepsy. The higher incidence of AML in older patients in our cohort might be explained by more frequent radiologic examinations in comparison to younger patients due to increasing comorbidities, and renal AML could have been detected incidentally. The main limitations of our study are the retrospective design and the small sample size. In summary, bilateral AML could be identified to be a risk factor for the occurrence of TSC. A previous study on histological findings in AML also concluded that pathologists should recognize that the presence of multiple AML is presumptive evidence for the diagnosis of TSC ( 17 ). Taking into consideration that the risk for haemorrhage from renal AML in patients with TSC is estimated between 25 and 50% ( 9 ), and that up to 20% of such patients present with a life threatening haemorrhage ( 18 ), the diagnosis of AML in radiologic examinations should raise the suspicion of TSC as an underlying multi-system disease, imply further investigations, and initiate targeted treatment with mTOR-inhibitors ( 13 ). Conclusions The presence of renal AML in patients with an age-range of 18–40 years should raise suspicion for concurrent TSC as the underlying cause. Therefore, particularly patients with bilateral renal AML should be referred for further testing for TSC, especially in light of the recent changes in the management of TSC and the option of a disease targeted therapy with mTOR-Inhibitors ( 13 ). Abbreviations AML Angiomyolipoma CKD Chronic Kidney Disease CT Computed Tomography IQR Interquartile Range MRI Magnetic Resonance Imaging mTOR mechanistic Target of Rapamycin OR Odds Ratio TSC Tuberous Sclerosis Complex Declarations Ethics approval and consent to participate The study protocol was approved by the Ethics Committee of Northwestern and Central Switzerland, with a waiver for individual informed consent (No. 2018-00037) Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research was supported by Novartis. Authors' contributions Hans-H. Seifert, Cyrill A. Rentsch: Conceptualization Julian Diethelm: Data curation Jan Ebbing, Christian Wetterauer, Julian Diethelm: Formal analysis Hans-H. Seifert: Funding acquisition Julian Diethelm: Investigation Hans-H. Seifert, Cyrill A. Rentsch: Methodology Hans-H. Seifert: Project administration Julian Diethelm: Resources Julian Diethelm: Software Hans-H. Seifert, Cyrill A. Rentsch, Daniel T. Boll: Supervision Hans-H. Seifert, Cyrill A. Rentsch, Daniel T. Boll: Validation Kathrin Bausch, Christian Wetterauer: Visualization Kathrin Bausch, Christian Wetterauer: Roles/Writing - original draft Kathrin Bausch, Christian Wetterauer, Julian Diethelm, Jan Ebbing, Daniel T. Boll, Patricia Dill, Cyrill A. Rentsch, Hans-H. Seifert: Writing - review & editing Acknowledgements The authors would like to thank Dr. Selina Ackermann from the University Hospital Basel for editorial assistance. References Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int. 2004;66(3):924-34. Consortium ECTS. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75(7):1305-15. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol. 2003;5(6):578-81. Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics. 2010;41(5):199-208. Curatolo P, editor. Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes. London: Cambridge University Press on behalf of Mac Keith Press; 2003. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998;13(12):624-8. Budde K, Gaedeke J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. Am J Kidney Dis. 2012;59(2):276-83. Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006;70(10):1777-82. Casper KA, Donnelly LF, Chen B, Bissler JJ. Tuberous sclerosis complex: renal imaging findings. Radiology. 2002;225(2):451-6. Fox CH, Voleti V, Khan LS, Murray B, Vassalotti J. A quick guide to evidence-based chronic kidney disease care for the primary care physician. Postgrad Med. 2008;120(2):E01-6. Nelson CP, Sanda MG. Contemporary diagnosis and management of renal angiomyolipoma. J Urol. 2002;168(4 Pt 1):1315-25. Ewalt DH, Diamond N, Rees C, Sparagana SP, Delgado M, Batchelor L, et al. Long-term outcome of transcatheter embolization of renal angiomyolipomas due to tuberous sclerosis complex. J Urol. 2005;174(5):1764-6. Moavero R, Romagnoli G, Graziola F, Curatolo P. Mammalian Target of Rapamycin Inhibitors and Life-Threatening Conditions in Tuberous Sclerosis Complex. Semin Pediatr Neurol. 2015;22(4):282-94. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):1345-56. Fujii Y, Ajima J, Oka K, Tosaka A, Takehara Y. Benign renal tumors detected among healthy adults by abdominal ultrasonography. Eur Urol. 1995;27(2):124-7. Stillwell TJ, Gomez MR, Kelalis PP. Renal lesions in tuberous sclerosis. J Urol. 1987;138(3):477-81. Eble JN. Angiomyolipoma of kidney. Semin Diagn Pathol. 1998;15(1):21-40. Kessler OJ, Gillon G, Neuman M, Engelstein D, Winkler H, Baniel J. Management of renal angiomyolipoma: analysis of 15 cases. Eur Urol. 1998;33(6):572-5. Cite Share Download PDF Status: Published Journal Publication published 31 Jan, 2021 Read the published version in BMC Nephrology → Version 1 posted Review # 1 received at journal 07 Dec, 2020 Reviewer # 2 agreed at journal 01 Dec, 2020 Reviewer # 1 agreed at journal 16 Nov, 2020 Editor assigned by journal 11 Nov, 2020 Reviewers invited by journal 11 Nov, 2020 Submission checks completed at journal 05 Nov, 2020 Editor invited by journal 04 Nov, 2020 First submitted to journal 13 Oct, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-103693","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":4431226,"identity":"13c84722-03f9-4432-994d-d70da4a30596","order_by":0,"name":"Kathrin Bausch","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYBACCQYGNgYGAzBiYGBssAELMePXwoyiJY1YLQxwLYcJa5FsP3/scUXBHQZz9jPGH37uOJ84f3YD4+cCPFqkeZLZDc8YPGOw7Mkxk+w9cztxw50DzNIz8GiRY0hmk2wwOMxgcCDHjJmxDahFIoGNmQefFv7HUC3n3xh/Zmw7lzh/BgEt0hIwW27kGEgzth1IbLhBQIvkjMdmIC08ljOelUn2tiUbb7hzsFkanxaJ84nPJBv+HJYz50/e/OFnm53s/NnNBz/j0wIDyGoYG4jQMApGwSgYBaMAHwAAJMlJgn6gihQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6253-0854","institution":"University Hospital Basel","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Kathrin","middleName":"","lastName":"Bausch","suffix":""},{"id":4431227,"identity":"633dbe06-8805-4c5b-b29a-91f9cc634624","order_by":1,"name":"Christian Wetterauer","email":"","orcid":"","institution":"University of Basel: Universitat Basel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Wetterauer","suffix":""},{"id":4431228,"identity":"181ce150-1e33-457f-9315-8de98d930f4d","order_by":2,"name":"Julian Diethelm","email":"","orcid":"","institution":"University of Basel: Universitat Basel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Julian","middleName":"","lastName":"Diethelm","suffix":""},{"id":4431229,"identity":"a3e0619f-bb2d-4929-8223-a856c1d76385","order_by":3,"name":"Jan Ebbing","email":"","orcid":"","institution":"Universitätsspital Basel: Universitatsspital Basel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Ebbing","suffix":""},{"id":4431230,"identity":"e5d9b680-adc8-46be-b140-d0f53097ba95","order_by":4,"name":"Daniel T. Boll","email":"","orcid":"","institution":"Universitätsspital Basel: Universitatsspital Basel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"T.","lastName":"Boll","suffix":""},{"id":4431231,"identity":"9f15f6bf-cb33-47f6-b234-2772778cdab0","order_by":5,"name":"Patricia Dill","email":"","orcid":"","institution":"UKBB Universitäts-Kinderspital: Universitats Kinderspital beider Basel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"","lastName":"Dill","suffix":""},{"id":4431232,"identity":"6f7bd6b4-94f7-4c47-b59a-9747bd70e3b4","order_by":6,"name":"Cyrill A. Rentsch","email":"","orcid":"","institution":"Universitätsspital Basel: Universitatsspital Basel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cyrill","middleName":"A.","lastName":"Rentsch","suffix":""},{"id":4431233,"identity":"8fc756af-f92b-4c89-9d6f-fb9b15ae76bb","order_by":7,"name":"Hans H. Seifert","email":"","orcid":"","institution":"Universitätsspital Basel: Universitatsspital Basel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hans","middleName":"H.","lastName":"Seifert","suffix":""}],"badges":[],"createdAt":"2020-11-05 21:18:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-103693/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-103693/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-021-02253-w","type":"published","date":"2021-01-31T15:01:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":3477744,"identity":"04788228-0287-43e6-a1a9-796c24e98907","added_by":"auto","created_at":"2020-11-10 00:07:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":239001,"visible":true,"origin":"","legend":"Patient Selection.\nAML, angiomyolipoma; CT, computed tomography; MRI, magnetic resonance imaging; TSC, tuberous sclerosis complex.","description":"","filename":"OnlineFigure1.Png","url":"https://assets-eu.researchsquare.com/files/rs-103693/v1/4f33cf0fd4170b49a5036783.Png"},{"id":13611971,"identity":"69947259-dec1-43be-b8f9-2b3a611ed0e4","added_by":"auto","created_at":"2021-09-17 06:31:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":476730,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-103693/v1/a5e43544-0b92-44b6-b5ab-a75564b2e076.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEnhancing Disease Awareness for Tuberous Sclerosis Complex in Patients with Radiologic Diagnosis of Renal Angiomyolipoma: An Observational Study\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eTuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder with a birth incidence of 1:6,000 and an estimated 1\u0026nbsp;million affected individuals worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). TSC is caused by an inactivating mutation in either the TSC-1 or the TSC-2 gene, which code for the proteins hamartin and tuberin (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). These proteins form a complex that activates the GTPase-activating protein Rheb to inhibit the mechanistic Target of Rapamycin (mTOR). The lack of mTOR-inactivation leads to an increase of protein synthesis, cellular metabolism, differentiation, and growth (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), which may affect virtually every organ. Therefore, TSC is very variable in its clinical manifestations (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Formerly, TSC was defined by Vogt\u0026rsquo;s triad of facial angiofibromas, mental retardation, and intractable epilepsy (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Nowadays, the clinical diagnosis is usually confirmed by either a set of major and minor diagnostic criteria or by the identification of a heterozygous pathogenic variant in TSC-1 or TSC-2 by molecular genetic testing (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Even though neurological (90%) and cutaneous (90%) manifestations, such as cortical tubers, epilepsy, giant cell astrocytoma, hydrocephalus, neurodevelopmental impairment, and facial angiofibromas (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), are the most common symptoms of TSC, 70 to 80% of TSC patients are also affected by renal angiomyolipoma (AML). Histologically, these benign tumours are composed of blood vessels, adipose tissue, and smooth muscle (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In contrast to sporadic AML, TSC-associated AML usually manifest in childhood and adolescence (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Growing renal AML pose a significant cause of mortality in TSC patients, since they bear the risk of severe life-threatening haemorrhage (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and impair the renal parenchyma, which leads to chronic kidney disease (CKD) and eventually end-stage renal disease. Given the current world population, the incidence of TSC, and the frequency of renal involvement, approximately 500,000 patients with TSC worldwide have at least CKD stage 1 (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). A literature review supports the impression that AML in patients with TSC tends to present earlier, with larger tumours of greater multiplicity, and more frequently in combination with haemorrhage, than in sporadic-type AML patients (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In general, surgical resection is avoided whenever possible in order to preserve renal function; interventions are required in case of persistent pain or acute or repeated bleeding episodes. The risk of bleeding increases with the size of AML. Therefore, beyond therapeutic nephron-sparing surgery or embolization, prophylactic intervention in large AML are recommended (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In TSC patients, new targeted treatment options with mTOR-inhibitors proved to be beneficial \u0026ndash; especially in AML patients (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAML are mostly diagnosed by computed tomography (CT), magnetic resonance imaging (MRI), or sonography (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), generally with near certainty due to their unique appearance. An imaging study involving 12,970 male and 4,971 female Japanese healthy adults identified renal AML in 13 (0.1%) males and 11 (0.22%) females (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, even though the correlation between AML and TSC has been described and TSC patients have an increased risk for AML-related complications, disease awareness for TSC in AML patients is low in clinical practice.\u003c/p\u003e \u003cp\u003eTherefore, the aim of this study was to investigate whether the radiologic diagnosis of renal AML can lead to the identification of TSC patients and thus increase disease awareness for TSC.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eWe performed an observational study at the departments of Urology and Radiology of the University Hospital Basel \u0026ndash; a tertiary care centre in Switzerland. We retrospectively analysed all CT, MRI, and sonography reports performed between 2010 and 2016.\u003c/p\u003e \u003cp\u003eThe study protocol was approved by the Ethics Committee of Northwestern and Central Switzerland, with a waiver for individual informed consent (No. 2018-00037). We followed the \u0026lsquo;Strengthening the Reporting of Observational Studies in Epidemiology\u0026rsquo; guidelines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection\u003c/h2\u003e \u003cp\u003eBetween January 2010 and December 2016, all CT, MRI, and sonography reports provided by the radiological reporting system were screened using the search terms \u0026ldquo;AML\u0026rdquo; and \u0026ldquo;angiomyolipoma\u0026rdquo;, in order to identify patients suffering from AML. The occurrence of renal AML was confirmed by manually reviewing the radiologic reports. In case of repeated exams, the exam with the first diagnosis was chosen for analysis. Only patients with completed datasets and patients aged 18\u0026nbsp;years and older were included.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData Collection and Definitions\u003c/h2\u003e \u003cp\u003eWe extracted all relevant information from in-house electronic medical records. The medical history was reviewed and patients with concurrent TSC (TSC+) were identified by clinical diagnosis in the medical history, independent of the method of initial testing for TSC (e.g. genetic testing, clinical presentation).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCorrelations were calculated using a non-normality Spearman\u0026rsquo;s rank correlation coefficient to determine the association between age, AML, and TSC. Correlation of nominal parameters (age group, AML, and TSC) were calculated using the phi-coefficient. All tests were performed at a significance level of α\u0026thinsp;=\u0026thinsp;0.05. Continuous data are shown as median with interquartile range (IQR). All analyses were performed with SPSS Statistics 19 (SPSS Inc., Chicago, Illinois, USA) and Graph Pad Prism Version 6.0 (GraphPad Software, La Jolla, California, USA).\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":"\u003cp\u003eThe search terms were identified in 1,122 (1.06%) of the overall 105,694 radiological reports, and the manual review of these reports led to the identification of 599 (53.4%) patients. Complete data were available for 547 (91.3%) of these patients, in 521 (95.2%; 357 (68.5%) females and 164 (31.5%) males) of which renal AML was present (AML+). The concurrent diagnosis of TSC was confirmed in 7 (1.3%) of these 521 patients (3 (0.6%) females and 4 (0.8%) males; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eMedian (IQR) AML\u0026thinsp;+\u0026thinsp;patients\u0026rsquo; age was 67.5 (19\u0026ndash;84) years, and median (IQR) AML+/TSC\u0026thinsp;+\u0026thinsp;patients\u0026rsquo; age was 28.3 (19\u0026ndash;42) years.\u003c/p\u003e\n\u003cp\u003eAML diagnosis was primarily confirmed by CT (295; 56.6%), followed by sonography (172; 33.0%) and MRI (54; 10.4%) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTable 1. Patient Characteristics.\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/58893_b39df98f09c4a4bb/58893_custom_files/img1604925905.png\" alt=\"\" /\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAML+, angiomyolipoma positive; CT, computed tomography; MRI, magnetic resonance imaging; TSC+, tuberous sclerosis complex positive. \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong all age groups, we found no significant correlation between presence of AML and concurrent TSC diagnosis (r\u0026thinsp;=\u0026thinsp;0.03; p\u0026thinsp;\u0026gt;\u0026thinsp;0.553). Younger age, however, significantly correlated with of the occurrence of TSC (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). 37 (7.1%) of the 521 AML\u0026thinsp;+\u0026thinsp;patients had an age range of 18\u0026ndash;40 years, 15 (2.9%) had an age range of 40\u0026ndash;45 years, and 475 (91.2%) were older than 45\u0026nbsp;years (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Prevalences of TSC in these age range-groups were 16.2% (6/37), 6.7% (1/15), and 0% (0/475), respectively.\u003c/p\u003e\n\u003cp\u003e4 (66.7%) and 2 (33.3%) of the 6 patients with an age range of 18\u0026ndash;40\u0026nbsp;years presented with bilateral and unilateral renal AML, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The TSC\u0026thinsp;+\u0026thinsp;patient with an age range of 40\u0026ndash;45\u0026nbsp;years also showed multiple bilateral AML. TSC\u0026thinsp;+\u0026thinsp;patients with bilateral renal AML had multiple AML lesions, whereas all TSC\u0026thinsp;+\u0026thinsp;patients with unilateral AML had only a single lesion. In AML+/TSC- patients, unilateral and bilateral AML was found in 83.9% (26/31) and 16.1% (5/31; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), respectively. Among the TSC- group, unilateral AML presented predominantly (92.3%; 24/26) and bilateral AML uniquely (100%; 5/5) as a single lesion (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAngiomyolipoma and tuberous sclerosis complex in the age group 18 to 40\u0026nbsp;years.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAML+\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTSC-\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTSC+\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-values\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunilateral\u003c/p\u003e\n\u003cp\u003ebilateral\u003c/p\u003e\n\u003cp\u003etotal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.9% (26/31)\u003c/p\u003e\n\u003cp\u003e16.1% (5/31)\u003c/p\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.3% (2/6)\u003c/p\u003e\n\u003cp\u003e66.7% (4/6)\u003c/p\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003cem\u003eAML+, angiomyolipoma positive; TSC+/-, tuberous sclerosis positive/negative.\u003c/em\u003e\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe presence of renal AML, either uni- or bilateral, significantly correlated with a concurrent TSC diagnosis (p\u0026thinsp;=\u0026thinsp;0.028). Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95%CI 3.2\u0026ndash;344.0; p\u0026thinsp;=\u0026thinsp;0.003) (but not unilateral AML (OR 0.09; 95%CI 0.01\u0026ndash;0.88; p\u0026thinsp;=\u0026thinsp;0.04)) to be a risk factor for the presence of TSC.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, we identified an overall TSC prevalence in AML\u0026thinsp;+\u0026thinsp;patients of 1.3%. Two thirds of the AML\u0026thinsp;+\u0026thinsp;patients were female and one third male (68.5% vs 31.5%). Accordingly, 0.6% of the male and 0.8% of the female AML\u0026thinsp;+\u0026thinsp;patients had concurrent TSC. These findings are in line with the literature: while the prevalence of TSC was similar in female and male patients, the clinical manifestation \u0026ndash; i.e., the prevalence of AML \u0026ndash; differed between genders. The higher prevalence of AML in females has been reported previously (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e). Sporadic AML is known to exhibit predominance in female patients as an effect of growth stimulation of oestrogen and progesterone receptors in AML (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWe found a significant positive correlation between younger age and TSC prevalence in AML\u0026thinsp;+\u0026thinsp;patients. Epidemiological studies regarding TSC patients show an increase of renal AML manifestation during childhood and adolescence (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). In our study, 37 AML\u0026thinsp;+\u0026thinsp;patients were within the age range of 18\u0026ndash;40 years, and the prevalence of TSC in this group was 16.2%. Those findings are in line with the results of prior studies, where 1% of all AML patients had concurrent TCS, but 10% of the AML patients with an age range of 18\u0026ndash;40\u0026nbsp;years (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eA previous longitudinal study demonstrated that 55% of paediatric TSC patients with a mean age of 6.9\u0026nbsp;years had some type of renal abnormality, and that this proportion even rose to 80% at a mean age of 10.5\u0026nbsp;years (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e). Renal AML was by far the most common form of involvement. The authors concluded that in TSC, renal involvement begins in infancy and increases with age. Studies have also demonstrated that the incidence of AML in patients with TSC increased with age and that rapid growth occurred in childhood and adolescence, with slower growth into adulthood (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e). Consequently, we expect that if patients\u0026thinsp;\u0026lt;\u0026thinsp;18\u0026nbsp;years would have been included in our study, more cases of TSC would have been identified.\u003c/p\u003e\n\u003cp\u003eIn our cohort, 66.7% of the TCS patients with an age range of 18\u0026ndash;40\u0026nbsp;year presented with bilateral renal AML and 33.3% with unilateral renal AML (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Multiple lesions were identified in all TSC\u0026thinsp;+\u0026thinsp;patients with bilateral AML, whereas primarily single lesions were found in both uni- and bilateral AML+/TSC- patients. The distribution of uni- and bilateral AML in TSC patients has already been investigated in the 1980s: 29% of the AML were unilateral, and 71% occurred on both sides (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e). Our findings are also in line with previous findings that demonstrated more bilateral AML and a higher multiplicity in AML patients with TSC than in AML patients without TSC (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn our study, the majority of AML (91.2%) was identified in patients under the age of 45\u0026nbsp;years. A previously published study investigating the AML incidence in TSC patients demonstrated a significant association between increasing age and the incidence of AML (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e). However, in our cohort, no patient above the age of 45\u0026nbsp;years had been diagnosed with TSC. These findings may indicate that TSC patients are underdiagnosed due to the formerly limited awareness for TSC and lost to follow-up. Furthermore, life expectancy of most TSC patients is limited to young adulthood due to malignancies and unexpected death in epilepsy. The higher incidence of AML in older patients in our cohort might be explained by more frequent radiologic examinations in comparison to younger patients due to increasing comorbidities, and renal AML could have been detected incidentally. The main limitations of our study are the retrospective design and the small sample size.\u003c/p\u003e\n\u003cp\u003eIn summary, bilateral AML could be identified to be a risk factor for the occurrence of TSC. A previous study on histological findings in AML also concluded that pathologists should recognize that the presence of multiple AML is presumptive evidence for the diagnosis of TSC (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTaking into consideration that the risk for haemorrhage from renal AML in patients with TSC is estimated between 25 and 50% (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e), and that up to 20% of such patients present with a life threatening haemorrhage (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e), the diagnosis of AML in radiologic examinations should raise the suspicion of TSC as an underlying multi-system disease, imply further investigations, and initiate targeted treatment with mTOR-inhibitors (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusions","content":" \u003cp\u003eThe presence of renal AML in patients with an age-range of 18\u0026ndash;40\u0026nbsp;years should raise suspicion for concurrent TSC as the underlying cause. Therefore, particularly patients with bilateral renal AML should be referred for further testing for TSC, especially in light of the recent changes in the management of TSC and the option of a disease targeted therapy with mTOR-Inhibitors (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eAML Angiomyolipoma\u003c/p\u003e\n\u003cp\u003eCKD Chronic Kidney Disease\u003c/p\u003e\n\u003cp\u003eCT Computed Tomography\u003c/p\u003e\n\u003cp\u003eIQR Interquartile Range\u003c/p\u003e\n\u003cp\u003eMRI Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003emTOR mechanistic Target of Rapamycin\u003c/p\u003e\n\u003cp\u003eOR Odds Ratio\u003c/p\u003e\n\u003cp\u003eTSC Tuberous Sclerosis Complex\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Ethics Committee of Northwestern and Central Switzerland, with a waiver for individual informed consent (No. 2018-00037)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by Novartis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHans-H. Seifert, Cyrill A. Rentsch: Conceptualization\u003c/p\u003e\n\u003cp\u003eJulian Diethelm: Data curation\u003c/p\u003e\n\u003cp\u003eJan Ebbing, Christian Wetterauer, Julian Diethelm: Formal analysis\u003c/p\u003e\n\u003cp\u003eHans-H. Seifert: Funding acquisition\u003c/p\u003e\n\u003cp\u003eJulian Diethelm: Investigation\u003c/p\u003e\n\u003cp\u003eHans-H. Seifert, Cyrill A. Rentsch: Methodology\u003c/p\u003e\n\u003cp\u003eHans-H. Seifert: Project administration\u003c/p\u003e\n\u003cp\u003eJulian Diethelm: Resources\u003c/p\u003e\n\u003cp\u003eJulian Diethelm: Software\u003c/p\u003e\n\u003cp\u003eHans-H. Seifert, Cyrill A. Rentsch, Daniel T. Boll: Supervision\u003c/p\u003e\n\u003cp\u003eHans-H. Seifert, Cyrill A. Rentsch, Daniel T. Boll: Validation\u003c/p\u003e\n\u003cp\u003eKathrin Bausch, Christian Wetterauer: Visualization\u003c/p\u003e\n\u003cp\u003eKathrin Bausch, Christian Wetterauer: Roles/Writing - original draft\u003c/p\u003e\n\u003cp\u003eKathrin Bausch, Christian Wetterauer, Julian Diethelm, Jan Ebbing, Daniel T. Boll, Patricia Dill, Cyrill A. Rentsch, Hans-H. Seifert: Writing - review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Dr. Selina Ackermann from the University Hospital Basel for editorial assistance.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int. 2004;66(3):924-34.\u003c/li\u003e\n\u003cli\u003eConsortium ECTS. Identification and characterization of the tuberous sclerosis gene on chromosome 16. 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Am J Kidney Dis. 2012;59(2):276-83.\u003c/li\u003e\n\u003cli\u003eRakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006;70(10):1777-82.\u003c/li\u003e\n\u003cli\u003eCasper KA, Donnelly LF, Chen B, Bissler JJ. Tuberous sclerosis complex: renal imaging findings. Radiology. 2002;225(2):451-6.\u003c/li\u003e\n\u003cli\u003eFox CH, Voleti V, Khan LS, Murray B, Vassalotti J. A quick guide to evidence-based chronic kidney disease care for the primary care physician. Postgrad Med. 2008;120(2):E01-6.\u003c/li\u003e\n\u003cli\u003eNelson CP, Sanda MG. Contemporary diagnosis and management of renal angiomyolipoma. J Urol. 2002;168(4 Pt 1):1315-25.\u003c/li\u003e\n\u003cli\u003eEwalt DH, Diamond N, Rees C, Sparagana SP, Delgado M, Batchelor L, et al. Long-term outcome of transcatheter embolization of renal angiomyolipomas due to tuberous sclerosis complex. J Urol. 2005;174(5):1764-6.\u003c/li\u003e\n\u003cli\u003eMoavero R, Romagnoli G, Graziola F, Curatolo P. Mammalian Target of Rapamycin Inhibitors and Life-Threatening Conditions in Tuberous Sclerosis Complex. Semin Pediatr Neurol. 2015;22(4):282-94.\u003c/li\u003e\n\u003cli\u003eCrino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):1345-56.\u003c/li\u003e\n\u003cli\u003eFujii Y, Ajima J, Oka K, Tosaka A, Takehara Y. Benign renal tumors detected among healthy adults by abdominal ultrasonography. Eur Urol. 1995;27(2):124-7.\u003c/li\u003e\n\u003cli\u003eStillwell TJ, Gomez MR, Kelalis PP. Renal lesions in tuberous sclerosis. J Urol. 1987;138(3):477-81.\u003c/li\u003e\n\u003cli\u003eEble JN. Angiomyolipoma of kidney. Semin Diagn Pathol. 1998;15(1):21-40.\u003c/li\u003e\n\u003cli\u003eKessler OJ, Gillon G, Neuman M, Engelstein D, Winkler H, Baniel J. Management of renal angiomyolipoma: analysis of 15 cases. Eur Urol. 1998;33(6):572-5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"angiomyolipoma, chronic kidney disease, renal angiomyolipoma, tuberous sclerosis, Tuberous Sclerosis Complex","lastPublishedDoi":"10.21203/rs.3.rs-103693/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-103693/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground\u003c/em\u003e\u003c/p\u003e\u003cp\u003eTuberous Sclerosis Complex (TSC) is a genetic disorder, with renal manifestations like angiomyolipoma (AML) occurring in 70-80% of patients. AML usually cause more complications in TCS patients than in non-TSC patients. However, AML patients are not routinely investigated for TSC.\u0026nbsp;Our aim was to retrospectively assess the correlation between radiologically diagnosed AML and TSC.\u003c/p\u003e\u003cp\u003e\u003cem\u003eMethods\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAll patients were stratified into AML related vs. unrelated to TSC. Correlations were calculated to determine the association between age, AML, and TSC. \u003c/p\u003e\u003cp\u003e\u003cem\u003eResults\u003c/em\u003e\u003c/p\u003e\u003cp\u003eComplete data were available for 521 patients with renal AML, in 7 of which the concurrent diagnosis of TSC was found. Younger age significantly positively correlated with the prevalence of TSC in AML patients (p\u0026lt;0.01). 37 (7%) of the 521 patients were within the age-range of 18-40 years, in which TSC occurred in 6 cases, 4 (66.7%) of which presented with multiple, bilateral renal AML (p\u0026lt;0.05), and 2 (33.3%) of which with a single, unilateral AML (p\u0026lt;0.05). In patients with AML but without TSC, unilateral AML was found in 83.9% and bilateral AML in 16.1% (p\u0026lt;0.05).\u0026nbsp;Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95% CI 3.2–344.0; p=0.003) (but not unilateral AML (OR 0.09; 95% CI 0.01–0.88; p=0.04)) to be a risk factor for TSC. \u003c/p\u003e\u003cp\u003e\u003cem\u003eConclusions\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe presence of bilateral AML in patients within the age-range of 18-40 years should raise suspicion for TSC as the underlying cause. Therefore, our advice is to refer patients with multiple bilateral renal AML for further investigations regarding TSC.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Enhancing Disease Awareness for Tuberous Sclerosis Complex in Patients with Radiologic Diagnosis of Renal Angiomyolipoma: An Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-11-10 00:07:36","doi":"10.21203/rs.3.rs-103693/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-12-08T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"reviewerAgreed","content":"","date":"2020-12-02T00:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-11-17T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-12T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-11-12T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-11-05T21:18:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-05T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-10-14T00:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2f7eba0c-3741-472f-85a6-8664879ec18e","owner":[],"postedDate":"November 10th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1016999,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2021-02-07T15:03:25+00:00","versionOfRecord":{"articleIdentity":"rs-103693","link":"https://doi.org/10.1186/s12882-021-02253-w","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2021-01-31 15:01:28","publishedOnDateReadable":"January 31st, 2021"},"versionCreatedAt":"2020-11-10 00:07:36","video":"","vorDoi":"10.1186/s12882-021-02253-w","vorDoiUrl":"https://doi.org/10.1186/s12882-021-02253-w","workflowStages":[]},"version":"v1","identity":"rs-103693","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-103693","identity":"rs-103693","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}