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Marlais M, Mekahli D. Tuberous sclerosis complex-associated kidney disease in children. Pediatr Nephrol 2025; 40:1871-1877. [PMID: 39814976 PMCID: PMC12031771 DOI: 10.1007/s00467-024-06642-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/05/2024] [Accepted: 12/12/2024] [Indexed: 01/18/2025]
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder which can have manifestations in the kidneys, along with other organ systems. Children with TSC may develop kidney lesions at any point during childhood, and typically these are angiomyolipomata (AML) and/or kidney cysts. Children may also have hypertension associated with TSC-associated kidney disease, and rarely reduced kidney function. New guidelines for the management of TSC-associated kidney disease in children and adults were published in 2024. This educational review summarises the relevant clinical aspects of these guidelines for paediatric nephrologists through a series of four clinical cases. These cases cover management of hypertension, frequency of follow-up and frequency of kidney imaging. Difficult clinical scenarios are reviewed, such as the management of TSC2-PKD1 contiguous gene syndrome and the management of large AMLs in children with TSC.
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Affiliation(s)
- Matko Marlais
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
- UCL Great Ormond Street Institute for Child Health, University College London, London, UK.
| | - Djalila Mekahli
- PKD Research Group, Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Louvain, Belgium
- Department of Paediatric Nephrology, University Hospitals Leuven, Louvain, Belgium
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Hagon-Nicod O, Fellmann F, Novy J, Lebon S, Wider C, Lazor R, Bonny O. Tuberous sclerosis: a survey in the canton of Vaud, Switzerland. Front Med (Lausanne) 2024; 11:1513619. [PMID: 39726678 PMCID: PMC11669681 DOI: 10.3389/fmed.2024.1513619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 11/28/2024] [Indexed: 12/28/2024] Open
Abstract
Aim of the study Tuberous sclerosis complex (TSC) is a genetic and multisystemic disorder that affects between 1/6'000 and 1/10'000 of newborns. Clinical criteria and/or genetic analysis establish the diagnosis. The mechanistic target of rapamycin (mTOR) inhibitors everolimus or sirolimus reduce the severity of several TSC-related clinical traits. We report here on the epidemiology and management of TSC patients in a large Swiss canton: the canton of Vaud. Method We extracted patient files containing the diagnostic code TSC in 2015 at the Lausanne University hospital (tertiary reference center for a population of about 755'000 people) and in specialized neurological institutions of the same region. Results We identified 52 patients with a diagnosis of TSC. The majority of the patients with a pathologic result in genetic testing were positive for a pathogenic variant in the TSC2 gene, including five cases of contiguous gene deletion syndrome of TSC2 and PKD1 causing both polycystic kidney disease and TSC. The most frequent clinical manifestations encountered were affecting the skin (87% of patients), the brain (83%), the heart (46%) and the kidneys (46%). Neuropsychiatric disorders were described in 56% of cases. At the time of data collection (2015), there were 2 patients using systemic mTOR inhibitors and 16 patients using topical mTOR inhibitors for dermatological features. Next, we compared this data with those of large published cohorts. While we found fewer cases than expected for the screened population, demographic as well as genetic data were overall similar to the literature. However, we observed that some clinical manifestations (renal, lung and neuropsychiatric disorders) were less frequently described in our cohort. Conclusion This work indicates that TSC and some of its clinical manifestations is under-reported. It raises concern that patients with mild manifestations are often not referred to reference centers with dedicated multidisciplinary group. The follow-up by expert board is instrumental in offering systematic screening of all putatively affected organs and to assess the eligibility for targeted treatment.
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Affiliation(s)
- Olivia Hagon-Nicod
- Department of Medicine, Service of Internal Medicine, Fribourg State Hospital, Fribourg, Switzerland
| | | | - Jan Novy
- Department of Medicine, Service of Neurology, Lausanne University Hospital, Lausanne, Switzerland
| | - Sébastien Lebon
- Unit of Pediatric Neurology and Neurorehabilitation, Woman-Mother-Child Department, Lausanne University Hospital, Lausanne, Switzerland
| | - Christian Wider
- Department of Medicine, Service of Neurology, Lausanne University Hospital, Lausanne, Switzerland
| | - Romain Lazor
- Department of Medicine, Service of Respiratory Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Olivier Bonny
- Department of Medicine, Service of Nephrology, Fribourg State Hospital, Fribourg, Switzerland
- Department of Medicine, Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland
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Limavady A, Marlais M. The extent of kidney involvement in paediatric tuberous sclerosis complex. Pediatr Nephrol 2024; 39:2927-2937. [PMID: 38832977 PMCID: PMC11349837 DOI: 10.1007/s00467-024-06417-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/16/2024] [Accepted: 05/16/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND Tuberous sclerosis (TSC)-associated kidney disease is a leading cause of mortality in adults with TSC. This study aimed to understand TSC features in children, particularly kidney involvement, to inform clinical care for this specific group. METHODS This retrospective cohort study included all paediatric (< 19 years) TSC cases at a large tertiary paediatric nephrology centre. Relevant data were collected from patients' records, statistical analyses were performed to identify associations between variables, survival probabilities were estimated with Kaplan‒Meier curves, and log-rank tests were conducted to assess survival differences among genetic mutations. RESULTS A total of 182 children with TSC were included. Among the 145 children with available kidney imaging data, 78.6% (114/145) exhibited kidney lesions. Angiomyolipomas (AMLs) were significantly more prevalent in the TSC2 mutation group (p = 0.018). Children with TSC2 mutations generally had poorer lesion-free survival than those with TSC1 mutations, but this difference was only significant for AMLs (p = 0.030). The change in size of largest AMLs increased with age and doubled in children above 9 years; a similar pattern was observed when stratified by genetic mutation. In contrast, kidney cysts exhibited two peaks: one in children under 5 years (2.31 mm/year) and the second in children between 15-19 years (2.82 mm/year). Chronic kidney disease was observed in 12.3% (10/81) of children, and high-risk AMLs above 3 cm were observed in 9% (13/145). CONCLUSIONS While TSC kidney disease emerges later in the disease course than neurological features, our findings emphasise the importance of kidney surveillance during childhood, including routine kidney imaging, kidney function, and blood pressure monitoring.
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Affiliation(s)
- Andrew Limavady
- Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Matko Marlais
- Great Ormond Street Institute of Child Health, University College London, London, UK.
- Department of Paediatric Nephrology, Great Ormond Street Hospital, London, UK.
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Wang W, Qiu D, Zhao Y, Wang Z, Wang X, Li Y, Liu Y, Liao Z, Zhang Y. New staging criteria predicting m-tor inhibitors treatment effect of renal angiomyolipoma in tuberous sclerosis complex patients. World J Urol 2024; 42:532. [PMID: 39302433 DOI: 10.1007/s00345-024-05235-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 08/13/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND We aimed to launched new staging criteria to predict mTOR inhibitors treatment effect of renal angiomyolipomas (r-AMLs) in TSC patients. METHODS 40 TSC patients with 69 r-AMLs were divided into two groups based on the efficacy of 6-month mTOR inhibitor treatment. Epidemiological data, therapeutic response, and predictive factors of enrolled patients were collected and analyzed. Age, sex, maximum diameter, maximum cross-sectional area (CSAmax), unenhanced mean CT value, enhanced mean CT value, and added value of enhanced CT of largest r-AML at baseline were assessed as potential influencing factors. Receiver operating characteristic (ROC) curve analysis and the area under the ROC curve (AUC) was used to estimate prediction power. RESULTS After 6 months of mTOR inhibitor treatment, the tumor reduction rates in the two groups were 55.87% and 16.44% (P < 0.001). At the start of treatment, the maximum diameters, CSAmax, added value of enhanced CT of the target lesion in two groups were 7.70 ± 0.73 cm vs. 13.18 ± 1.23 cm(P = 0.028), 57.40 ± 10.76cm2 vs. 167.29 ± 33.09cm2 (P = 0.015), and 62.32 ± 5.03HU vs. 33.06 ± 3.13HU (P = 0.009), respectively. AUCs of CSAmax, added value of enhanced CT, and combination of both were 0.8024, 0.7672, and 0.8116, respectively (P < 0.001). Cut-off values of CSAmax combined with the added value of enhanced CT were 40cm2 and 46HU. AUCs of maximum diameters, combination of maximum diameters and added value of enhanced CT were 0.7600 and 0.8100, respectively (P < 0.001), with cut-off values of 6.6 cm and 46 HU. CONCLUSION New staging criteria, based on CSAmax and added value of enhanced CT, can predict the treatment efficiency of m-TOR inhibitors for r-AMLs in TSC patients. A simplified version based on maximum diameter and added value of enhanced CT of lesion has also been proposed.
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Affiliation(s)
- Wenda Wang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China
| | - Dongxu Qiu
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada
| | - Yang Zhao
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China
| | - Zhan Wang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China
| | - Xu Wang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China
| | - Yanan Li
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China
| | - Yi Liu
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China
| | - Zhangcheng Liao
- Department of Urolog, Xiangya Hospital, Central South University, 410008, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, China.
| | - Yushi Zhang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing, 100730, PR China.
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Rubtsova VI, Chun Y, Kim J, Ramirez CB, Jung S, Choi W, Kelly ME, Lopez ML, Cassidy E, Rushing G, Aguiar DJ, Lau WL, Ahdoot RS, Smith M, Edinger AL, Lee SG, Jang C, Lee G. Circulating biomarkers of kidney angiomyolipoma and cysts in tuberous sclerosis complex patients. iScience 2024; 27:110265. [PMID: 39027368 PMCID: PMC11255849 DOI: 10.1016/j.isci.2024.110265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/04/2024] [Accepted: 06/11/2024] [Indexed: 07/20/2024] Open
Abstract
Patients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based methods that are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified 7 highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. These data highlight AML/cysts blood biomarkers for TSC patients and offers valuable metabolic insights into the disease.
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Affiliation(s)
- Varvara I. Rubtsova
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Yujin Chun
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Joohwan Kim
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Cuauhtemoc B. Ramirez
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Sunhee Jung
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Wonsuk Choi
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Miranda E. Kelly
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Miranda L. Lopez
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
| | | | | | | | - Wei Ling Lau
- Division of Nephrology, Department of Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Rebecca S. Ahdoot
- Division of Nephrology, Department of Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Moyra Smith
- Division of Genetics and Metabolism, Department of Pediatrics, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Aimee L. Edinger
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, CA, USA
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Sang-Guk Lee
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Cholsoon Jang
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA
| | - Gina Lee
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
- Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA
- Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA
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Goedken AM, Ismail WW, Barrett LDG, Harshman LA. Kidney transplantation in patients with tuberous sclerosis complex. Pediatr Transplant 2024; 28:e14765. [PMID: 38778713 PMCID: PMC11125526 DOI: 10.1111/petr.14765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/08/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Tuberous sclerosis complex (TSC) is a disorder of the mammalian target of the rapamycin (mTOR) pathway associated with the development of multisystem tumors, including renal angiomyolipoma (AML). These renal tumors are benign by nature but locally invasive and carry a risk for the progression of chronic kidney disease (CKD) to end stage kidney disease (ESKD). The frequency of subsequent renal transplantation in this population is largely uncharacterized, although single-center data suggests that 5%-15% of adult TSC patients are kidney transplant recipients. METHODS This retrospective cohort study utilized United Network for Organ Sharing (UNOS) data. We included candidates waitlisted between 1987 and 2020 for a first kidney transplant with TSC-associated kidney failure. We utilized descriptive statistics to characterize the frequency of first-time kidney transplant waitlisting and transplantation among persons with TSC and the Fine-Gray subdistribution hazard model to evaluate characteristics associated with progression from waitlist. RESULTS We identified 200 TSC-associated kidney failure patients within the waitlist cohort. Of these, 12 were pediatric patients. Two-thirds (N = 134) of waitlisted persons were female. One hundred forty patients received a transplant with a median waitlist time of 2 years. Younger age at waitlisting was associated with a greater probability of progressing to transplant (HR 0.98 [95% CI: 0.96-0.99]). 91.8% of kidney transplant recipients survived 1-year post-transplant with a functioning allograft. CONCLUSIONS The majority of patients with TSC who are waitlisted for a kidney transplant progress onto transplantation with excellent 1-year post transplant patient and allograft survival.
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Affiliation(s)
- Amber M. Goedken
- Department of Pharmacy Practice and Science, University of Iowa College of Pharmacy, Iowa City, IA
| | - Wesam W. Ismail
- Department of Pharmacy Practice and Science, University of Iowa College of Pharmacy, Iowa City, IA
| | - Lucas DG Barrett
- Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine; Iowa City, IA
- Medical Scientist Training Program, University of Iowa Carver College of Medicine; Iowa City, IA
- Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA
| | - Lyndsay A. Harshman
- Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine; Iowa City, IA
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Mekahli D, Müller RU, Marlais M, Wlodkowski T, Haeberle S, de Argumedo ML, Bergmann C, Breysem L, Fladrowski C, Henske EP, Janssens P, Jouret F, Kingswood JC, Lattouf JB, Lilien M, Maleux G, Rozenberg M, Siemer S, Devuyst O, Schaefer F, Kwiatkowski DJ, Rouvière O, Bissler J. Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: a consensus statement by the ERKNet Working Group for Autosomal Dominant Structural Kidney Disorders and the ERA Genes & Kidney Working Group. Nat Rev Nephrol 2024; 20:402-420. [PMID: 38443710 DOI: 10.1038/s41581-024-00818-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2024] [Indexed: 03/07/2024]
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout the body. Management of TSC is challenging because patients have a multifaceted systemic illness with prominent neurological and developmental impact as well as potentially severe kidney, heart and lung phenotypes; however, every organ system can be involved. Adequate care for patients with TSC requires a coordinated effort involving a multidisciplinary team of clinicians and support staff. This clinical practice recommendation was developed by nephrologists, urologists, paediatric radiologists, interventional radiologists, geneticists, pathologists, and patient and family group representatives, with a focus on TSC-associated kidney manifestations. Careful monitoring of kidney function and assessment of kidney structural lesions by imaging enable early interventions that can preserve kidney function through targeted approaches. Here, we summarize the current evidence and present recommendations for the multidisciplinary management of kidney involvement in TSC.
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Affiliation(s)
- Djalila Mekahli
- PKD Research Group, Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
- Department of Paediatric Nephrology, University Hospitals Leuven, Leuven, Belgium.
| | - Roman-Ulrich Müller
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Rare Diseases Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Matko Marlais
- UCL Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Tanja Wlodkowski
- Division of Paediatric Nephrology, Center for Paediatrics and Adolescent Medicine, University Hospital, Heidelberg, Germany
| | - Stefanie Haeberle
- Division of Paediatric Nephrology, Center for Paediatrics and Adolescent Medicine, University Hospital, Heidelberg, Germany
| | - Marta López de Argumedo
- Basque Office for Health Technology Assessment, (OSTEBA), Basque Government, Vitoria-Gasteiz, Spain
| | - Carsten Bergmann
- Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany
| | - Luc Breysem
- Department of Radiology, University Hospital of Leuven, Leuven, Belgium
| | - Carla Fladrowski
- Associazione Sclerosi Tuberosa ASP, Rome, Italy
- European Tuberous Sclerosis Complex Association (ETSC), Oestrich-Winkel, Germany
| | - Elizabeth P Henske
- Center for LAM Research and Clinical Care, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Peter Janssens
- Department of Nephrology and Arterial Hypertension, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium
| | - François Jouret
- Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium
- Interdisciplinary Group of Applied Genoproteomics, Cardiovascular Sciences, University of Liège, Liège, Belgium
| | - John Christopher Kingswood
- Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St Georges University of London, London, UK
| | - Jean-Baptiste Lattouf
- Department of Surgery-Urology, CHUM-Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Marc Lilien
- Department of Paediatric Nephrology, Wilhelmina Children´s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Geert Maleux
- Department of Radiology, University Hospitals Leuven, Leuven, Belgium
| | - Micaela Rozenberg
- European Tuberous Sclerosis Complex Association (ETSC), Oestrich-Winkel, Germany
- Associação de Esclerose Tuberosa em Portugal, Lisbon, Portugal
| | - Stefan Siemer
- Department of Urology and Paediatric Urology, Saarland University, Homburg, Germany
| | - Olivier Devuyst
- Department of Physiology, Mechanisms of Inherited Kidney Disorders, University of Zurich, Zurich, Switzerland
- Institute for Rare Diseases, Saint-Luc Academic Hospital, UC Louvain, Brussels, Belgium
| | - Franz Schaefer
- Division of Paediatric Nephrology, Center for Paediatrics and Adolescent Medicine, University Hospital, Heidelberg, Germany
| | - David J Kwiatkowski
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Olivier Rouvière
- Department of Radiology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Université Lyon 1, Lyon, France, Faculté de médecine Lyon Est, Lyon, France
| | - John Bissler
- Department of Paediatrics, University of Tennessee Health Science Center and Le Bonheur Children's Hospital, Memphis, TN, USA.
- Children's Foundation Research Institute (CFRI), Le Bonheur Children's Hospital, Memphis, TN, USA.
- Paediatric Medicine Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
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Limavady A, Marlais M. Nutritional status as a predictive factor for paediatric tuberous sclerosis complex-associated kidney angiomyolipomas: a retrospective analysis. Eur J Pediatr 2024; 183:2563-2570. [PMID: 38483608 PMCID: PMC11098920 DOI: 10.1007/s00431-024-05520-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/09/2024] [Accepted: 03/09/2024] [Indexed: 05/19/2024]
Abstract
The purpose of this study is to determine the predictive factors of tuberous sclerosis complex (TSC)-associated kidney disease and its progression in children. Retrospective review of children with TSC in a tertiary children's hospital was performed. Relevant data were extracted, and Cox proportional hazards regression was used to establish predictors of kidney lesions. Logistic regression was conducted to identify factors predicting chronic kidney disease (CKD) and high-risk angiomyolipomas (above 3 cm). Kidney imaging data were available in 145 children with TSC; of these, 79% (114/145) had abnormal findings. The only significant predictive factor for cyst development was being female (HR = 0.503, 95% CI 0.264-0.956). Being female (HR = 0.505, 95% CI 0.272-0.937) and underweight (HR = 0.092, 95% CI 0.011-0.800) both lowers the risk of having angiomyolipomas, but TSC2 mutations (HR = 2.568, 95% CI 1.101-5.989) and being obese (HR = 2.555, 95%CI 1.243-5.255) increases risks. Ten (12%) of 81 children with kidney function tested demonstrate CKD stages II-V, and only angiomyolipomas above 3 cm predict CKD. Additionally, 13/145 (9%) children had high-risk angiomyolipomas, whereby current age (adjusted odds ratio (aOR) 1.015, 95% CI 1.004-1.026) and being overweight/obese (aOR 7.129, 95% CI 1.940-26.202) were significantly associated with angiomyolipomas above 3 cm. CONCLUSIONS While gender and genotype are known predictors, this study includes the novel finding of nutritional status as a predictor of TSC-associated kidney disease. This study sheds light on a possible complex interplay of hormonal influences, obesity, and kidney angiomyolipomas growth, and further investigations focusing on the impact of nutritional status on TSC-associated kidney disease are warranted. WHAT IS KNOWN • Gender and genotype are well-studied predictive factors in TSC kidney disease. WHAT IS NEW • Nutritional status may influence the development and the progression of kidney lesions in children with TSC and should not be overlooked. • Management guidelines of TSC-associated kidney disease can address nutritional aspects.
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Affiliation(s)
- Andrew Limavady
- Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Matko Marlais
- Great Ormond Street Institute of Child Health, University College London, London, UK.
- Department of Paediatric Nephrology, Great Ormond Street Hospital, London, UK.
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Zhang J, Zhen T, Jian H, Yang J, Zhang N. Arterial embolization in the treatment of multiple renal and hepatic hamartomas with spontaneous hemorrhage and 2-year follow-up: a case report. J Med Case Rep 2024; 18:208. [PMID: 38622693 PMCID: PMC11020817 DOI: 10.1186/s13256-024-04368-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 01/06/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Hamartoma is a common benign tumor that usually occurs in the kidney, liver, lung, and pancreas. Large renal hamartomas may spontaneously rupture and hemorrhage, which is potentially life-threatening. CASE PRESENTATION This report describes a 46-year-old Han Chinese female patient with multiple renal and hepatic hamartomas with rupture and hemorrhage of giant hamartoma in the left kidney. She underwent arterial embolization three times successively, and her condition was stable during the 2-year follow-up. This report includes a review of the relevant literature CONCLUSIONS: the findings in this report and previous literature suggest that arterial embolization can not only rapidly treat hamartoma hemorrhage in the acute phase but can also effectively control multiple lesions in the long term after repeated multisite arterial embolization.
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Affiliation(s)
- Jianhua Zhang
- Department of Interventional Radiology, Fengjie County People's Hospital, Chongqing, China
| | - Tao Zhen
- Department of Oncology, Fengjie County People's Hospital, Chongqing, China
| | - Hongmei Jian
- Department of Oncology, Fengjie County People's Hospital, Chongqing, China
| | - Jinlan Yang
- Department of Oncology, Fengjie County People's Hospital, Chongqing, China
| | - Ni Zhang
- Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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10
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Kluiving MW, Peeters EFHI, Lely TA, van Oorschot N, de Ranitz-Greven WL. The effect of pregnancy on renal angiomyolipoma; a world of knowledge to gain, specifically in women with TSC. BMC Nephrol 2024; 25:113. [PMID: 38519911 PMCID: PMC10960455 DOI: 10.1186/s12882-024-03483-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/25/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Women are counseled preconceptionally about the potential risks of rAML progression and chance of complications during and due to pregnancy. However, a systematic search investigating the evidence on which this advice is based does not exist. The aim of this systematic review is to determine the effect of pregnancy on renal angiomyolipoma (rAML) size and risk of haemorrhage in patients with tuberous sclerosis complex (TSC). METHODS We searched PubMed, EMBASE, Medline and ClinicalTrials.gov using terms for "renal angiomyolipoma" and "pregnancy". English-language articles published between January 1st 2000, and December 31st 2020 of which full-text was available were included. The initial search resulted in 176 articles. After the screening process we included 45 case reports and 1 retrospective study. For the retrospective study we assessed the risk of bias using the Newcastle-Ottawa Scale. We included articles about renal AML and pregnancy with and without an established diagnosis of TSC. From these articles we recorded the rAML sizes and rAML complications. RESULTS Seven case reports, from a total of 45 case reports, provided follow-up data on renal AML size (these were all cases of renal AML without a known diagnosis of TSC). Of these cases, renal AML size decreased in one patient, was stable in one patient, increased in three patients and fluctuated in two others. Renal AML size of women who suffered a haemorrhage were significantly larger (12.1 ± 4.6 cm) than rAMLs of women who did not suffer a haemorrhage (8.3 ± 3.2 cm). Data from the retrospective study showed no difference in renal complications between the women with and without a history of pregnancy. Haemorrhage occurred in 30% of the women with a history of pregnancy (n = 20) and in 11% in the patients without a history of pregnancy (n = 2), however this retrospective study had methodological limitations. CONCLUSION The effect of pregnancy on renal AML size and complications in patients with TSC is unclear. More research is needed to determine the risk of pregnancy on TSC-associated kidney disease in TSC patient.
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Affiliation(s)
- Marlou W Kluiving
- Department of Internal Medicine, Center of Expertise for Tuberous Sclerosis Complex, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Evelien F H I Peeters
- Department of Internal Medicine, Center of Expertise for Tuberous Sclerosis Complex, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Titia A Lely
- Department of Obstetrics and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Niek van Oorschot
- Department of Radiology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Wendela L de Ranitz-Greven
- Department of Internal Medicine, Center of Expertise for Tuberous Sclerosis Complex, University Medical Center Utrecht, Utrecht, The Netherlands
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11
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Long HY, Qian ZP, Lan Q, Xu YJ, Da JJ, Yu FX, Zha Y. Human pluripotent stem cell-derived kidney organoids: Current progress and challenges. World J Stem Cells 2024; 16:114-125. [PMID: 38455108 PMCID: PMC10915962 DOI: 10.4252/wjsc.v16.i2.114] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/18/2023] [Accepted: 01/29/2024] [Indexed: 02/26/2024] Open
Abstract
Human pluripotent stem cell (hPSC)-derived kidney organoids share similarities with the fetal kidney. However, the current hPSC-derived kidney organoids have some limitations, including the inability to perform nephrogenesis and lack of a corticomedullary definition, uniform vascular system, and coordinated exit pathway for urinary filtrate. Therefore, further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development, regeneration, disease modeling, and drug screening. In this review, we discussed recent advances in the generation of hPSC-derived kidney organoids, how these organoids contribute to the understanding of human kidney development and research in disease modeling. Additionally, the limitations, future research focus, and applications of hPSC-derived kidney organoids were highlighted.
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Affiliation(s)
- Hong-Yan Long
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Zu-Ping Qian
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Qin Lan
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yong-Jie Xu
- Department of Laboratory Medicine, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China
| | - Jing-Jing Da
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China
| | - Fu-Xun Yu
- Key Laboratory of Diagnosis and Treatment of Pulmonary Immune Diseases, National Health Commission, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China
| | - Yan Zha
- Graduate School, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China.
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12
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Tovani-Palone MR, Bistagnino F, Shah PA. Multidisciplinary team for patients with neurocutaneous syndromes: The little discussed importance of dentistry. Clinics (Sao Paulo) 2024; 79:100332. [PMID: 38364341 PMCID: PMC10881307 DOI: 10.1016/j.clinsp.2024.100332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/12/2023] [Accepted: 01/14/2024] [Indexed: 02/18/2024] Open
Abstract
Neurocutaneous syndromes comprise a heterogeneous group of congenital or hereditary conditions that are known to be associated with the risk of different disorders and complications. Two of the most common neurocutaneous syndromes are Neurofibromatosis type 1 (NF1) and Tuberous Sclerosis Complex (TSC). Although there appears to be a general consensus on the importance of a multidisciplinary approach in managing these cases, there is still very little emphasis in discussions addressed in the literature on the role of dentistry in accordance with the perspective of comprehensive care. Evidence-based propositions, together with a broad discussion of new insights in this regard, should have the ability to strongly impact related future perspectives, aiming for greater advances and better outcomes for these patients. In this review article, the authors discuss updated general aspects of NF1 and TSC, and the potential additional roles of dentistry, in addition to addressing suggestions for actions in dentistry at related levels of care, as well as priorities for future research.
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Affiliation(s)
- Marcos Roberto Tovani-Palone
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India.
| | - Filippo Bistagnino
- Department of Medical Biotechnology and Translational Medicine, International Medical School, Università degli Studi di Milano, Milan, Italy
| | - Pritik A Shah
- Bangalore Medical College and Research Institute, Bangalore, India
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13
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Cockerell I, Christensen J, Hoei-Hansen CE, Holst L, Grenaa Frederiksen M, Issa-Epe AI, Nedregaard B, Solhoff R, Heimdal K, Johannessen Landmark C, Lund C, Nærland T. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet J Rare Dis 2023; 18:377. [PMID: 38042867 PMCID: PMC10693167 DOI: 10.1186/s13023-023-02982-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 11/18/2023] [Indexed: 12/04/2023] Open
Abstract
BACKGROUND The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. RESULTS The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. CONCLUSIONS Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.
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Affiliation(s)
- Ine Cockerell
- Department of Rare Disorders and Disabilities, National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, Pb 4950, 0424, Nydalen, Oslo, Norway.
| | - Jakob Christensen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Neurology, Aarhus University Hospital, Affiliated Member of the European Reference Network EpiCARE, Aarhus, Denmark
| | - Christina E Hoei-Hansen
- Department of Clinical Medicine, Copenhagen University, Copenhagen, Denmark
- Department of Paediatrics, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Lotte Holst
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Aart Imran Issa-Epe
- Section of Abdominal Radiology, Department of Radiology, Oslo University Hospital, Oslo, Norway
| | - Bård Nedregaard
- Section of Neuroradiology, Department of Radiology, Oslo University Hospital, Oslo, Norway
| | - Ragnar Solhoff
- Department of Neurology, Sørlandet Hospital, Arendal, Norway
| | - Ketil Heimdal
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Cecilie Johannessen Landmark
- Department of Pharmacy, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
- The National Center for Epilepsy (SSE), Member of the ERN EpiCare, Oslo University Hospital, Oslo, Norway
- Section for Clinical Pharmacology, SSE, Department of Pharmacology, Oslo University Hospital, Oslo, Norway
| | - Caroline Lund
- Department of Rare Disorders and Disabilities, National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, Pb 4950, 0424, Nydalen, Oslo, Norway
| | - Terje Nærland
- K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- NevSom, Department of Rare Disorders and Disabilities, Oslo University Hospital, Oslo, Norway
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14
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Kronick J, Gabril MY, House AA. Microscopic Kidney Disease in Tuberous Sclerosis Complex and Treatment With mTOR Inhibition. Am J Kidney Dis 2023; 82:772-775. [PMID: 37532078 DOI: 10.1053/j.ajkd.2023.04.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/02/2023] [Accepted: 04/27/2023] [Indexed: 08/04/2023]
Abstract
Declining kidney function in tuberous sclerosis complex (TSC) is often attributed to large lesions, including angiomyolipomas (AMLs) and cysts, that encroach on the normal parenchyma or that require intervention and loss of parenchyma from surgical debulking or embolization. Consequently, research on inhibitors of the mammalian target of rapamycin (mTOR), a protein complex implicated in TSC pathophysiology for its role in promoting cell growth and proliferation, has largely focused on their ability to reduce AML size. Clinical guidelines distilled from this research limit mTOR inhibition as a first-line treatment to patients with large AMLs. However, chronic kidney disease (CKD) occurs in patients without large AMLs or a history of renal intervention. Alternate mechanisms postulated for CKD in TSC may suggest a role for mTOR inhibition in this population. In this report, we present 2 cases of a microscopic variant of TSC kidney disease causing declining kidney function, as well as anecdotal evidence for the use of mTOR inhibition to improve kidney function in the absence of large AMLs. We highlight the importance of annual kidney function assessment in patients with TSC and suggest a low threshold for kidney biopsy in patients with declining glomerular filtration rate without a clear etiology clinically or radiographically.
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Affiliation(s)
- Jami Kronick
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Manal Y Gabril
- Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Andrew A House
- Division of Nephrology, Department of Medicine, Western University and London Health Sciences Centre, London, Ontario, Canada.
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15
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Gallo-Bernal S, Kilcoyne A, Gee MS, Paul E. Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions. Pediatr Nephrol 2023; 38:3253-3264. [PMID: 36445479 DOI: 10.1007/s00467-022-05820-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 11/02/2022] [Accepted: 11/02/2022] [Indexed: 12/02/2022]
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.
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Affiliation(s)
- Sebastian Gallo-Bernal
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
- Department of Radiology, Harvard Medical School, Boston, MA, USA
| | - Aoife Kilcoyne
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
- Department of Radiology, Harvard Medical School, Boston, MA, USA
| | - Michael S Gee
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
- Department of Radiology, Harvard Medical School, Boston, MA, USA
| | - Elahna Paul
- Department of Pediatric Nephrology, Massachusetts General Hospital, Boston, MA, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
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16
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Gupta S, Stanton ML, Reynolds JP, Whaley RD, Herrera-Hernandez L, Jimenez RE, Cheville JC. Reprint of: lessons from histopathologic examination of nephrectomy specimens in patients with tuberous sclerosis complex: cysts, angiomyolipomas & renal cell carcinoma. Hum Pathol 2023; 133:136-152. [PMID: 36894367 DOI: 10.1016/j.humpath.2023.02.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 09/08/2022] [Indexed: 03/09/2023]
Abstract
Renal manifestations in patients with tuberous sclerosis complex (TSC) include cysts, angiomyolipoma, and renal cell carcinoma. Unlike many hereditary predisposition syndromes, the spectrum of renal tumors in TSC patients (including both angiomyolipoma and renal cell carcinoma) is broad, with significant morphologic heterogeneity. An improved understanding of histopathologic findings in TSC patients and associated clinicopathologic correlates has significant implications not just in establishing a diagnosis of TSC, but also in the recognition of sporadic tumors occurring secondary to somatic alterations of TSC1/TSC2/MTOR pathway genes and accurate prognostication. In this review, we have discussed issues relevant to clinical management based on histopathologic findings in nephrectomy specimens from patients with TSC. This includes discussions related to screening for TSC, diagnosis of PKD1/TSC2 contiguous gene deletion syndrome, the morphologic spectrum of angiomyolipoma and renal epithelium-derived neoplasia, including the risk of disease progression.
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Affiliation(s)
- Sounak Gupta
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
| | - Melissa L Stanton
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ, 85054, USA.
| | - Jordan P Reynolds
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, 32224, USA.
| | - Rumeal D Whaley
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
| | | | - Rafael E Jimenez
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
| | - John C Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
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17
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Luo C, Zhang Y, Zhang YS, Zhang MX, Ning J, Chen MF, Li Y, Qi L, Zu XB, Li YL, Cai Y. Renal phenotypes correlate with genotypes in unrelated individuals with tuberous sclerosis complex in China. Orphanet J Rare Dis 2022; 17:288. [PMID: 35870981 PMCID: PMC9308181 DOI: 10.1186/s13023-022-02443-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 07/14/2022] [Indexed: 11/22/2022] Open
Abstract
Purpose To explore the relationship between the genotype and renal phenotype in a Chinese cohort and guide clinical decision-making for treating tuberous sclerosis complex (TSC). Materials and methods We reviewed 173 patients with definite TSC at three centers in China from September 2014 to September 2020. All the patients underwent TSC1 and TSC2 genetic testing as well as renal phenotypic evaluation. All analyses were performed using the SPSS software, version 19.0, with a cut-off P value of 0.05 considered statistically significant. Results We identified variants in 93% (161/173) cases, including 16% TSC1 and 77% TSC2 variants. Analysis of the relationship between the genotype and renal phenotype, revealed that those with TSC2 variants were more likely to develop severe renal AML (> 4) (P = 0.044). In terms of treatment, TSC2 variants were more likely to undergo nephrectomy/partial nephrectomy (P = 0.036) and receive mTOR medication such as everolimus (P < 0.001). However, there was no significant difference between the two groups in terms of their response to the everolimus treatment. Conclusion Patients with TSC2 variants exhibit more severe renal phenotypes, especially those associated with renal angiomyolipomas (AML), and they often require nephrectomy/partial nephrectomy or mTOR medication. Detection of the genotype is helpful in TSC management. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02443-1.
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18
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Gupta S, Stanton ML, Reynolds JP, Whaley RD, Herrera-Hernandez L, Jimenez RE, Cheville JC. Lessons from histopathologic examination of nephrectomy specimens in patients with tuberous sclerosis complex: cysts, angiomyolipomas, and renal cell carcinoma. Hum Pathol 2022; 129:123-139. [PMID: 36115585 DOI: 10.1016/j.humpath.2022.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 09/08/2022] [Indexed: 02/07/2023]
Abstract
Renal manifestations in patients with tuberous sclerosis complex (TSC) include cysts, angiomyolipoma, and renal cell carcinoma. Unlike many hereditary predisposition syndromes, the spectrum of renal tumors in TSC patients (including both angiomyolipoma and renal cell carcinoma) is broad, with significant morphologic heterogeneity. An improved understanding of histopathologic findings in TSC patients and associated clinicopathologic correlates has significant implications not just in establishing a diagnosis of TSC, but also in the recognition of sporadic tumors occurring secondary to somatic alterations of TSC1/TSC2/MTOR pathway genes and accurate prognostication. In this review, we have discussed issues relevant to clinical management based on histopathologic findings in nephrectomy specimens from patients with TSC. This includes discussions related to screening for TSC, diagnosis of PKD1/TSC2 contiguous gene deletion syndrome, the morphologic spectrum of angiomyolipoma and renal epithelium-derived neoplasia, including the risk of disease progression.
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Affiliation(s)
- Sounak Gupta
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
| | - Melissa L Stanton
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ, 85054, USA.
| | - Jordan P Reynolds
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, 32224, USA.
| | - Rumeal D Whaley
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
| | | | - Rafael E Jimenez
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
| | - John C Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
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19
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Vaughan RM, Kordich JJ, Chan CY, Sasi NK, Celano SL, Sisson KA, Van Baren M, Kortus MG, Aguiar DJ, Martin KR, MacKeigan JP. Chemical Biology Screening Identifies a Vulnerability to Checkpoint Kinase Inhibitors in TSC2-Deficient Renal Angiomyolipomas. Front Oncol 2022; 12:852859. [PMID: 35359406 PMCID: PMC8960247 DOI: 10.3389/fonc.2022.852859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/14/2022] [Indexed: 11/13/2022] Open
Abstract
The tuberous sclerosis complex (TSC) is a rare genetic syndrome and multisystem disease resulting in tumor formation in major organs. A molecular hallmark of TSC is a dysregulation of the mammalian target of rapamycin (mTOR) through loss-of-function mutations in either tumor suppressor TSC1 or TSC2. Here, we sought to identify drug vulnerabilities conferred by TSC2 tumor-suppressor loss through cell-based chemical biology screening. Our small-molecule chemical screens reveal a sensitivity to inhibitors of checkpoint kinase 1/2 (CHK1/2), regulators of cell cycle, and DNA damage response, in both in vitro and in vivo models of TSC2-deficient renal angiomyolipoma (RA) tumors. Further, we performed transcriptional profiling on TSC2-deficient RA cell models and discovered that these recapitulate some of the features from TSC patient kidney tumors compared to normal kidneys. Taken together, our study provides a connection between mTOR-dependent tumor growth and CHK1/2, highlighting the importance of CHK1/2 inhibition as a potential antitumor strategy in TSC2-deficient tumors.
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Affiliation(s)
- Robert M Vaughan
- Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
| | - Jennifer J Kordich
- Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Chun-Yuan Chan
- Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Nanda K Sasi
- Graduate Program in Genetics, Michigan State University, East Lansing, MI, United States
| | - Stephanie L Celano
- Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States.,Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
| | - Kellie A Sisson
- Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Megan Van Baren
- Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Matthew G Kortus
- Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States
| | - Dean J Aguiar
- Preclinical Research, Tuberous Sclerosis Complex (TSC) Alliance, Silver Springs, MD, United States
| | - Katie R Martin
- Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States.,Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
| | - Jeffrey P MacKeigan
- Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States.,Center for Cancer & Cell Biology, Van Andel Research Institute, Grand Rapids, MI, United States.,Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
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20
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Vargiami E, Stabouli S, Sidira C, Kyriazi M, Anastasiou A, Notopoulos A, Zafeiriou D. Blood pressure and glomerular filtration rate in youth with tuberous sclerosis complex. Eur J Pediatr 2022; 181:1465-1472. [PMID: 34988664 DOI: 10.1007/s00431-021-04333-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 11/03/2022]
Abstract
UNLABELLED Renal involvement is very common in tuberous sclerosis complex (TSC) and is characterized by the development of angiomyolipoma and cysts. The aims of the present study were to assess kidney function and clinical features of renal involvement in TSC, including kidney function and blood pressure (BP) levels in children, adolescents and young adults. Non-selected patients with a definite diagnosis of TSC attending the paediatric neurology outpatient department of a tertiary hospital were included in a cross-sectional study. All participants had a renal imaging study within 6 months of ambulatory blood pressure (BP) and glomerular filtration rate (GFR) assessment. Data on demographics, history, genotype, kidney function at diagnosis and last imaging were collected. Twenty patients were enrolled in this study with a median age of 15 years (IQR range 9 to 18). About 23.5% of the participants had ambulatory hypertension. Systolic BP levels correlated significantly with GFRDTPA values despite the absence of hyperfiltration. Patients that developed hypertension and possibly those with angiomyolipoma or cysts had higher GFR levels in childhood and adolescence. All the patients with ambulatory hypertension had angiomyolipoma or cysts on renal imaging studies. CONCLUSIONS Hypertension may present with increased frequency in young patients with kidney disease associated with TSC. Routine ambulatory BP measurement should be part of the annual clinical assessment in patients with TSC. WHAT IS KNOWN • Nearly half of the patients with TSC have a premature decline in their renal function in their fifth decade of life. • Hypertension and hyperfiltration have been proposed as modifiable factors of progression of renal decline in patients with TSC-related renal disease. WHAT IS NEW • Hypertension is prevalent in youth with tuberous sclerosis complex. • SBP levels have a positive relation with GFR levels within the normal range of GFRDTPA values.
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Affiliation(s)
- Efthymia Vargiami
- First Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Hippokratio Hospital, 49 Konstantinoupoleos Str, 54642, Thessaloniki, Greece
| | - Stella Stabouli
- First Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Hippokratio Hospital, 49 Konstantinoupoleos Str, 54642, Thessaloniki, Greece.
| | - Christina Sidira
- First Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Hippokratio Hospital, 49 Konstantinoupoleos Str, 54642, Thessaloniki, Greece
| | - Maria Kyriazi
- First Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Hippokratio Hospital, 49 Konstantinoupoleos Str, 54642, Thessaloniki, Greece
| | | | | | - Dimitrios Zafeiriou
- First Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Hippokratio Hospital, 49 Konstantinoupoleos Str, 54642, Thessaloniki, Greece
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Kidney Transplantation in a Patient With Tuberous Sclerosis Complex: A Case Report. Transplant Proc 2022; 54:1148-1151. [DOI: 10.1016/j.transproceed.2022.02.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/07/2022] [Accepted: 02/18/2022] [Indexed: 11/20/2022]
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Luo C, Ye WR, Shi W, Yin P, Chen C, He YB, Chen MF, Zu XB, Cai Y. Perfect match: mTOR inhibitors and tuberous sclerosis complex. Orphanet J Rare Dis 2022; 17:106. [PMID: 35246210 PMCID: PMC8895788 DOI: 10.1186/s13023-022-02266-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 02/20/2022] [Indexed: 12/22/2022] Open
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that presents with diverse and complex clinical features and involves multiple human systems. TSC-related neurological abnormalities and organ dysfunction greatly affect the quality of life and can even result in death in patients with TSC. It is widely accepted that most TSC-related clinical manifestations are associated with hyperactivation of the mammalian target of rapamycin (mTOR) pathway caused by loss‑of‑function mutations in TSC1 or TSC2. Remarkable progress in basic and translational research has led to encouraging clinical advances. Although mTOR inhibitors (rapamycin/everolimus) demonstrate great potential in TSC management, two major concerns hamper their generalized application. One is the frequent manifestation of adverse events, such as stomatitis, infections, and menstrual disorders; and the other is the poor response in certain patients. Thus, indicators are required to effectively predict the efficacy of mTOR inhibitors. Herein, we have summarized the current utilization of mTOR inhibitors in the treatment of TSC and focused on their efficacy and safety, in an attempt to provide a reference to guide the treatment of TSC. Hyperactivation of mammalian target of rapamycin (mTOR) is essential in the
pathogenesis of tuberous sclerosis complex (TSC) and can serve as a therapeutic
target. mTOR inhibitors have shown considerable success in multiple clinical trials for the treatment of TSC, including neurological, pulmonary, cardiac, renal, and cutaneous
phenotypes. mTOR inhibitors are associated with adverse events, which should be considered
during the management of TSC. Indicators to predict mTOR inhibitor efficacy are required to select patients who
are likely to benefit from such therapy.
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Affiliation(s)
- Cong Luo
- Department of Urology, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Wen-Rui Ye
- Department of Neurosurgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Wei Shi
- Department of Dermatology, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Ping Yin
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Chen Chen
- Department of Pediatrics, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Yun-Bo He
- Department of Urology, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Min-Feng Chen
- Department of Urology, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Xiong-Bin Zu
- Department of Urology, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Yi Cai
- Department of Urology, Disorders of Tuberous Sclerosis Complex (TSC) Multidisciplinary Team, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha City, 410008, Hunan Province, People's Republic of China.
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Salama M, Mostafa A, Salama N, Alabrak M, Abdalaleem S, Hanafy A. Renal AML Surgically Treated 33 Cases. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.7300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Renal angiomyolipoma (RAML) is a rare benign neoplasm with a prevalence varying between 0.2% and 0.6% and a strong female predilection. They occur as sporadic, isolated entities in 80% of cases. The remaining 20% of angiomyolipomas (AMLs) develop in association with tuberous sclerosis complex or pulmonary lymphangioleiomyomatosis.
AIM: We describe our 10-year experience with AML and discuss the treatment strategies employed at our center.
METHODS: The medical records of all 33 patients with pathologically confirmed RAML treated either by nephrectomy or nephron-sparing surgery at our center over 10 years were reviewed for patient age and sex, tumor location and size, association with TBS.
RESULTS: There were 28 females (84.8%) and 5 males (15.2%) with a median age that was 52 (range 22–74) years at the time of surgery. Thirty patients (90.9%) had sporadic isolated AML, and 3 patients (9.1%) had AML with TBS. The tumor was in the right kidney in 15 (45.5%) patients, in the left kidney in 17 (51.5%) patients, and bilateral in only 1 patient (3%) who was diagnosed with TBS. At presentation, flank pain was the main symptom in 23 patients (69.7%).
CONCLUSIONS: Surgical resection of RAML provides short-term symptomatic relieve and long-term survival.
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Tan L, Xu Y, Lan G, Wang H, Liang Z, Zhang Z, Tian Q, Hou Y, Zhao Y, Xie X. Absence of TSC1 Accelerates CD8 + T cell-mediated Acute Cardiac Allograft Rejection. Aging Dis 2022; 13:1562-1575. [PMID: 36186130 PMCID: PMC9466980 DOI: 10.14336/ad.2022.0224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/24/2022] [Indexed: 11/18/2022] Open
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by inactivating mutations in TSC1 or TSC2.Patients with TSC often require organ transplantation after organ failure. TSC1 serves as an important control node in immune cell development and responses; however, its effect on T cells in transplant immunity has not yet been explored. Here, we characterized the effect of TSC1 deficiency in T cells on acute allograft rejection using a mouse cardiac transplantation model. We observed compromised allograft survival in mice with TSC1-deficient T cells. Notably, the allografts in mice transferred with TSC1-deficient CD8+T cells showed accelerated acute allograft rejection. TSC1 deficiency triggered the increased accumulation of CD8+ T cells in allografts due to augmented infiltration caused by increased CXCR3 expression levels and elevated in-situ proliferation of TSC1-deficient CD8+ T cells. Compared to CD8+ T cells from wild-type (WT) mice, TSC1-deficient CD8+ T cells exhibited enhanced cell proliferation and increased expression levels of interferon-γ and granzyme B after alloantigen stimulation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), is used to treat patients with TSC and prevent rejection after solid-organ transplantation. Although rapamycin induced most cardiac allografts to survive beyond 100 d in WT mice, rapamycin-treated cardiac allografts in TSC1-deficient mice were rejected within 60 d. These results suggest that TSC1-deficient recipients may be more resistant to rapamycin-mediated immunosuppression during organ transplantation. Collectively, TSC1 significantly accelerates acute allograft rejection by enhancing the alloreactivity of CD8+ T cells, making them more resistant to mTOR inhibitor-mediated immunosuppression.
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Affiliation(s)
- Liang Tan
- Department of Kidney Transplantation, Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China.
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
| | - Gongbin Lan
- Department of Kidney Transplantation, Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China.
| | - Hongxia Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhanfeng Liang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
| | - Zhaoqi Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
| | - Qianchuan Tian
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
| | - Yangxiao Hou
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
| | - Xubiao Xie
- Department of Kidney Transplantation, Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China.
- Correspondence should be addressed to: Dr. Xubiao Xie, Department of Kidney Transplantation, Second Xiangya Hospital of Central South University, Changsha 410011, China. E-mail: .
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Chung NKX, Metherall P, McCormick JA, Simms RJ, Ong ACM. OUP accepted manuscript. Clin Kidney J 2022; 15:1160-1168. [PMID: 35754971 PMCID: PMC9214570 DOI: 10.1093/ckj/sfac037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Indexed: 12/05/2022] Open
Abstract
Background Everolimus is a potential alternative to embolization and nephrectomy for managing tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML). In 2016, National Health Service England approved its use through regional centres for renal AML ≥30 mm showing interval growth. Evidence of lesion stabilization or reduction after 6 months is mandated for continuation of long-term treatment. Methods From November 2016 to June 2021, all potentially eligible adult TSC patients with AML across Yorkshire and Humber were referred for assessment and monitoring. Eligible patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a follow-up MRI scan after 6 months on everolimus. Dose titration was guided by trough levels and lesion responsiveness using a new 3D MRI volumetric protocol. Results Of 28 patients commencing treatment, 19 tolerated everolimus for >3 months. Overall, 11 patients (40%) discontinued treatment, mostly due to recurrent infections (42%) and allergic reactions (25%). Sixty-eight percent required dose adjustments from the initiating dose (10 mg) due to sub-optimal trough levels (38%), minimal AML response (15%) or adverse events (47%). 3D volumetric assessment confirmed a reduction in AML volume of a pre-selected index lesion in all treatment-naïve cases (n = 14), showing superiority over 2D measurements of lesion diameter. Conclusion In this cohort, everolimus promoted AML regression in all patients who tolerated the drug for >6 months with stabilization observed over 3 years. Trough levels enabled individual dose titration to maximize responsiveness and minimize side effects. The use of 3D MRI assessment of lesion volume was superior to 2D measurements of lesion diameter in monitoring treatment response.
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Affiliation(s)
- Noelle K X Chung
- The Medical School, University of Sheffield, Sheffield, UK
- Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Peter Metherall
- 3D Lab, Medical Imaging and Medical Physics, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Janet A McCormick
- Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Roslyn J Simms
- Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Skrzypczyk P, Wabik AM, Szyszka M, Józwiak S, Bombiński P, Jakimów-Kostrzewa A, Brzewski M, Pańczyk-Tomaszewska M. Early Vascular Aging in Children With Tuberous Sclerosis Complex. Front Pediatr 2021; 9:767394. [PMID: 34912759 PMCID: PMC8667666 DOI: 10.3389/fped.2021.767394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/09/2021] [Indexed: 11/13/2022] Open
Abstract
Objectives: Experimental data indicate that activating mutations in the mTOR (mammalian target of rapamycin) pathway may lead to abnormal arterial wall structure. Vascular anomalies like arterial stenoses are reported in pediatric patients with tuberous sclerosis complex (TSC). In addition, large renal lesions (angiomyolipoma-AML and cysts) are risk factors for arterial hypertension in adult patients with TSC. This study aimed to assess blood pressure, including central blood pressure and arterial damage (early vascular aging-EVA) in children with TSC. Materials and Methods: In a group of 33 pediatric patients with TSC (11.13 ± 4.03 years, 15 boys, 18 girls), we evaluated peripheral and central office blood pressure, 24-h ambulatory blood pressure, and arterial damage: aortic pulse wave velocity (aPWV) [m/s], [Z-score], augmentation index (AIx75HR [%]), common carotid artery intima-media thickness (cIMT) [mm], [Z-score], stiffness of common carotid artery (E-tracking), renal lesions in magnetic resonance and ultrasonography, and selected biochemical parameters. The control group consisted of 33 healthy children (11.23 ± 3.28 years, 15 boys, 18 girls). Results: In TSC group 7 (21.2%) children had arterial hypertension, 27 (81.8%) children had renal angiomyolipomas, 26 (78.8%)-renal cysts, and 4 (12.1%) patients were treated with mTOR inhibitors (2 patients with everolimus and 2 patients with sirolimus) at the moment of evaluation. Children with TSC had higher central systolic blood pressure (AoSBP) (98.63 ± 9.65 vs. 90.45 ± 6.87 [mm Hg], p < 0.001), cIMT (0.42 ± 0.05 vs. 0.39 ± 0.03 [mm], p = 0.011), cIMT Z-score (0.81 ± 1.21 vs. 0.16 ± 0.57, p = 0.007), aPWV (4.78 ± 0.81 vs. 4.25 ± 0.56 [m/s], p = 0.003) and aPWV Z-score (-0.14 ± 1.15 vs. -0.96 ± 0.87, p = 0.002) compared to healthy children, without differences in AIx75HR (8.71 ± 15.90 vs. 5.24 ± 11.12 [%], p = 0.319) and stiffness of common carotid artery. In children with TSC AoSBP correlated positively with serum cystatin C concentration (r = 0.377, p = 0.030) and with maximum diameter of renal cyst (R = 0.419, p = 0.033); mean arterial pressure (MAP) 24 h Z-score correlated with serum cystatin C concentration (R = 0.433, p = 0.013); and aPWV Z-score with daily urinary albumin loss [mg/24 h] (R = 0.412, p = 0.029). Conclusions: Children with tuberous sclerosis complex are at risk of elevated central blood pressure and early vascular aging. In children with TSC, blood pressure and arterial stiffness are related to renal involvement.
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Affiliation(s)
- Piotr Skrzypczyk
- Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Maria Wabik
- Department of Pediatrics and Nephrology, Medical University of Warsaw, Warsaw, Poland
| | - Michał Szyszka
- Department of Pediatrics and Nephrology, Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Sergiusz Józwiak
- Department of Pediatric Neurology, Medical University of Warsaw, Warsaw, Poland
| | | | | | - Michał Brzewski
- Department of Pediatric Radiology, Medical University of Warsaw, Warsaw, Poland
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Peng JH, Tu HP, Hong CH. A population-based study to estimate survival and standardized mortality of tuberous sclerosis complex (TSC) in Taiwan. Orphanet J Rare Dis 2021; 16:335. [PMID: 34344419 PMCID: PMC8330058 DOI: 10.1186/s13023-021-01974-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/19/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Tuberous sclerosis complex (TSC) is an autosomal dominant disease with systemic manifestations, which can cause significant mortality and morbidity. Population-based epidemiological studies on TSC mortality and survival remain scarce, though several recent studies provide evidence that TSC survival rates are high and disease prognosis is fair for most patients. This study aims to estimate the life expectancy and mortality statistics in Taiwanese TSC patients, investigate prognosis and associations of TSC mortality based on demographic variables, and compare these results to past literature, especially for Asian patients. METHODS Taiwanese National Health Insurance (NHI) insurees can obtain Catastrophic Illness Certificates (CIC) for certain eligible diseases to waive copayments after diagnosis by two independent physicians. CIC holders for TSC during 1997-2010 were identified from the NHI Research Database. Queries on enrollment (CIC acquisition) age, endpoint (end of query period or death) age, sex, and comorbidities were obtained. Patients were separated into cohorts (endpoint age, sex, and age of diagnosis), and analyzed accordingly. RESULTS 471 patients (232 male, 239 female) were identified, of which 14 died. Compared to literature, patients showed similar demographics (age range, diagnosis age, sex distribution); similar manifestations and prevalence (epilepsy, intellectual disability, renal disease); lower disease prevalence (1 in 63,290); lower mortality (0.21% per year); and near-identical standardized mortality ratio (4.99). A cumulative mortality of 4.08% was found over 14 years, though mortality plateaued at 7 years post-enrollment, suggesting a good overall survival rate; comparable with previous studies in Asian patients. Enrollment age was a significant prognostic factor, with late-enrollment (age > 18) patients at higher risk for all-cause mortality (Hazard ratio = 6.54). Average remaining lifetime was significantly lower than the general population, and decreased with age. CONCLUSIONS This study reports a population-based disease database, highlights the importance of diagnosis age in prognosis prediction, and suggests the role of renal manifestations in mortality. Furthermore, it corroborates recent TSC studies in the Asian population in terms of survival. Overall, physician vigilance, early diagnosis, and careful monitoring are beneficial for disease outcome and patient survival.
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Affiliation(s)
- Jui-Hui Peng
- Department of Dermatology, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, 112 Taiwan
- Department of Medical Education, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 833 Taiwan
| | - Hung-Pin Tu
- Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, 807 Taiwan
| | - Chien-Hui Hong
- Department of Dermatology, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, 112 Taiwan
- Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung City, 813 Taiwan
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Leite T, Pazinato LV, Vidal MJDA, Freitas DD, Leal Filho JMDM. Endovascular treatment of intrarenal aneurysms bleeding and angiomyolipomas in a patient with tuberous sclerosis and polycystic kidney disease. J Bras Nefrol 2021; 45:111-115. [PMID: 34328493 PMCID: PMC10139728 DOI: 10.1590/2175-8239-jbn-2021-0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 06/14/2021] [Indexed: 11/22/2022] Open
Abstract
Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are conditions related to renal failure that can rarely occur in association as a contiguous gene syndrome. Angiomyolipomas (AMLs) are renal tumors strongly related to TSC that may rupture and cause life-threatening bleedings. We present a patient with TSC, ADPKD, and renal AMLs with persistent hematuria requiring blood transfusion. The persistent hematuria was successfully treated through endovascular embolization, a minimally invasive nephron sparing technique.
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Affiliation(s)
- Túlio Leite
- Universidade de São Paulo, Instituto do Coração, Departamento de Radiologia, São Paulo, SP, Brasil
| | - Lucas Vatanabe Pazinato
- Universidade de São Paulo, Faculdade de Medicina, Departamento de Radiologia, Unidade de Radiologia Intervencionista, São Paulo, SP, Brasil
| | | | - Danielo de Freitas
- Hospital Santa Genoveva, Departamento de Urologia, Uberlândia, MG, Brasil
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Renal tumors in tuberous sclerosis complex. Pediatr Nephrol 2021; 36:1427-1438. [PMID: 33006051 DOI: 10.1007/s00467-020-04775-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/11/2020] [Accepted: 09/10/2020] [Indexed: 01/19/2023]
Abstract
Tuberous sclerosis complex (TSC) is a multisystem hereditary disorder characterized by the growth of benign tumors (hamartomas) in multiple organs, including the kidneys. Renal angiomyolipomas (AML) are a major diagnostic feature of TSC and are present in the majority of patients by adulthood. However, AML are usually asymptomatic during childhood when neurological and developmental manifestations are the main source of morbidity. Kidney manifestations of TSC have historically been the main cause of morbidity and mortality of adults with TSC. The recognition that the complications of TSC are caused by dysregulation of the mammalian target of rapamycin (mTOR) pathway has led to an enormous progress in the management of patients with TSC in the last two decades, the establishment of diagnostic guidelines, and trials which have shown the therapeutic benefit of mTOR inhibitors. Kidney surveillance of children with TSC now provides the opportunity for timely interventions to reduce the impact of TSC in adulthood. In this review, we discuss the current management of kidney tumors associated with TSC, including the diagnosis, surveillance, and treatment options for these lesions. We also present outcome data from international registries demonstrating the effectiveness of the current management strategies. With clear management guidelines and efficient treatment of kidney tumors, we envisage that the long-term outcomes of patients with TSC will further improve in the future.
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Gupta S, Jimenez RE, Herrera-Hernandez L, Lohse CM, Thompson RH, Boorjian SA, Leibovich BC, Cheville JC. Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients. Mayo Clin Proc 2021; 96:1470-1489. [PMID: 33526281 DOI: 10.1016/j.mayocp.2020.11.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/07/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC). PATIENTS AND METHODS The Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML). RESULTS A total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm. CONCLUSION The identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.
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Affiliation(s)
- Sounak Gupta
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
| | - Rafael E Jimenez
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | - John C Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
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Ruiz Guerrero E, Ledo Cepero MJ, Ojeda Claro AV, Soto Delgado M, Álvarez-Ossorio Fernández JL. Renal angiomyolipoma and tuberous sclerosis complex: long-term safety and efficacy outcomes of Everolimus therapy. Actas Urol Esp 2021; 45:264-272. [PMID: 33637375 DOI: 10.1016/j.acuro.2020.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/25/2020] [Accepted: 11/10/2020] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Renal angiomyolipoma is a frequent manifestation of Tuberous Sclerosis Complex (TSC), for which everolimus therapy has been recently established as a novel non-invasive therapeutic option. As there are limited real life and long-term data, the analysis of our experience provides added value in terms of safety and efficacy. MATERIAL AND METHODS Descriptive analysis of our experience in patients with giant bilateral renal angiomyolipomas, in the context of TSC, treated with 10 mg oral everolimus daily, during a median of 71.5 months. We evaluated the following parameters: response rate and duration, reduction of kidney size and lesions, prevention of complications and presentation of toxicity and its cause. RESULTS We confirm the effectiveness of treatment in 4 young patients, with multiple, bilateral angiomyolipomas of a median of 12 (5-19) cm maximum diameter, from June 2013 to date, after continuous reduction in lesion size, a decrease of 30% of the volume in 75% at six months and 50% in half of the subjects at two years, still showing drug response. Absence of complications such as bleeding or glomerular filtration rate decline in the long term, with a favorable safety profile, without interruptions and with mild-moderate, non-cumulative adverse effects, mostly within the first year of treatment. CONCLUSION Everolimus is a safe and effective therapeutic option for renal angiomyolipoma and various manifestations of TSC, which has been reproduced in real life with six years of follow-up.
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Affiliation(s)
- E Ruiz Guerrero
- Unidad de Uro-Oncología, Servicio Urología, Hospital Universitario Puerta del Mar, INIBICA (Instituto de Investigación e Innovación Biomédica), Cádiz, España.
| | - M J Ledo Cepero
- Unidad de Uro-Oncología, Servicio Urología, Hospital Universitario Puerta del Mar, INIBICA (Instituto de Investigación e Innovación Biomédica), Cádiz, España
| | - A V Ojeda Claro
- Unidad de Uro-Oncología, Servicio Urología, Hospital Universitario Puerta del Mar, INIBICA (Instituto de Investigación e Innovación Biomédica), Cádiz, España
| | - M Soto Delgado
- Unidad de Uro-Oncología, Servicio Urología, Hospital Universitario Puerta del Mar, INIBICA (Instituto de Investigación e Innovación Biomédica), Cádiz, España
| | - J L Álvarez-Ossorio Fernández
- Unidad de Uro-Oncología, Servicio Urología, Hospital Universitario Puerta del Mar, INIBICA (Instituto de Investigación e Innovación Biomédica), Cádiz, España
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The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures. Sci Rep 2021; 11:8493. [PMID: 33875750 PMCID: PMC8055687 DOI: 10.1038/s41598-021-87930-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 04/01/2021] [Indexed: 02/02/2023] Open
Abstract
Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.
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Pfirmann P, Combe C, Rigothier C. [Tuberous sclerosis system: A review]. Rev Med Interne 2021; 42:714-721. [PMID: 33836894 DOI: 10.1016/j.revmed.2021.03.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/11/2021] [Accepted: 03/07/2021] [Indexed: 10/21/2022]
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects different organs and caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. TSC1 or TSC2 gene mutation lead to dysfunction of hamartin or tuberin, respectively. Hamartin and tuberin form a protein complex that helps regulate cellular proliferation. These proteins form a complex that constitutively inhibits the mammalian target of rapamycin (mTOR) signaling pathway, leading to permanent activation of mTOR signaling within all TSC-associated lesions. Major features of TSC include tumors of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. These disorders are usually diagnosed in children and adults. Specific guidelines for diagnosis, surveillance, and management have been proposed by the International Tuberous Sclerosis Complex Consensus Group. Several randomized controlled trials led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas, refractory epilepsy and pulmonary lymphangioleiomyomatosis.
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Affiliation(s)
- P Pfirmann
- Service de néphrologie, transplantation, dialyse et aphérèses, hôpital Pellegrin, CHU de Bordeaux, place Amélie-Raba-Léon, 33076 Bordeaux, France; Inserm U1026, BioTis, université de Bordeaux, 33076 Bordeaux, France.
| | - C Combe
- Service de néphrologie, transplantation, dialyse et aphérèses, hôpital Pellegrin, CHU de Bordeaux, place Amélie-Raba-Léon, 33076 Bordeaux, France; Inserm U1026, BioTis, université de Bordeaux, 33076 Bordeaux, France
| | - C Rigothier
- Service de néphrologie, transplantation, dialyse et aphérèses, hôpital Pellegrin, CHU de Bordeaux, place Amélie-Raba-Léon, 33076 Bordeaux, France; Inserm U1026, BioTis, université de Bordeaux, 33076 Bordeaux, France
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Goedken AM, Samuels JA, Sato TS, Harshman LA. Kidney Imaging Surveillance in Commercially Insured Patients With Tuberous Sclerosis Complex. Pediatr Neurol 2021; 117:21-26. [PMID: 33647778 DOI: 10.1016/j.pediatrneurol.2020.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/15/2020] [Accepted: 12/21/2020] [Indexed: 10/22/2022]
Abstract
BACKGROUND Kidney disease has historically been the primary source of early mortality in adults with tuberous sclerosis complex (TSC). Kidney imaging surveillance promotes early detection of lesions requiring intervention. We describe kidney imaging frequency in relationship to patient-level characteristics for commercially insured patients with TSC in the United States. METHODS This retrospective observational study used 2003 to 2016 enrollment and claims data from a de-identified fully insured commercial health insurer. Patients with TSC less than 65 years were included. The patient-level kidney imaging rate was calculated as the number of kidney imaging procedures divided by length of continuous enrollment. A multiple linear regression model was used to determine the relationship between imaging rate and progression of TSC-associated kidney disease, number of specialists seen, and nephrologist care. RESULTS At least half of the 70 patients with TSC included in the study were aged 16 years or younger. Over a follow-up period of up to 14 years, the median kidney imaging rate was 0.13 procedures per year with 43% (N = 30) of patients lacking evidence of kidney imaging during the observation period. Imaging frequency increased with progression of TSC-associated kidney disease, more specialists, and nephrologist care (P < 0.05 for all three in regression model). CONCLUSIONS A substantial percentage of patients with TSC in the United States are at risk for delayed detection of kidney manifestations due to infrequent kidney imaging surveillance. Multispecialty care, including neurologists, may positively affect kidney surveillance rates.
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Affiliation(s)
- Amber M Goedken
- Division of Health Services Research, College of Pharmacy, University of Iowa, Iowa City, Iowa.
| | - Joshua A Samuels
- Division of Pediatric Nephrology and Hypertension, McGovern Medical School, University of Texas Health Science Center, Houston, Texas
| | - Takashi S Sato
- Division of Pediatric Radiology, Stead Family Children's Hospital, University of Iowa, Iowa City, Iowa
| | - Lyndsay A Harshman
- Division of Pediatric Nephrology, University of Iowa Stead Family Department of Pediatrics, University of Iowa, Iowa City, Iowa
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Stockinger J, Strzelczyk A, Nemecek A, Cicanic M, Bösebeck F, Brandt C, Hamer H, Intravooth T, Steinhoff BJ. Everolimus in adult tuberous sclerosis complex patients with epilepsy: Too late for success? A retrospective study. Epilepsia 2021; 62:785-794. [PMID: 33534134 DOI: 10.1111/epi.16829] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 01/17/2023]
Abstract
OBJECTIVE There is evidence that everolimus (EVE) significantly reduces seizure frequency in epilepsy patients with tuberous sclerosis complex (TSC). Given that TSC-related proliferative processes are more dynamic during brain development, seizure outcomes of patients treated with EVE may be age-related and may be less convincing in adult patients. The aim of this study was to assess the effectiveness and the safety profile of EVE in adults in clinical practice. METHODS We performed a multicenter retrospective chart review of TSC subjects with active epilepsy who started EVE in adulthood (≥18 years of age) at seven German epilepsy centers. The primary endpoint was the retention rate after 6 months. RESULTS A total of 45 subjects with a mean age of 31.6 ± 11.1 years at EVE start fulfilled the inclusion criteria. Retention rate after 6 months was 98% (43/44 evaluable subjects). Response rate (seizure reduction ≥ 50%) was 33% (14/43 evaluable subjects; four completely seizure-free). We did not find a significant relationship between epilepsy outcome parameters and patient age at EVE start. Adverse events were reported in 19 subjects and were judged to be serious in six patients. Three patients died during the observation period. SIGNIFICANCE Evidence suggests that EVE is an effective add-on treatment for epilepsy in adult TSC patients, surprisingly without any age limit to individual benefit. A strong age-dependent effect within the period of adulthood seems unlikely. Even if there was no proof of a causal relationship between deaths and EVE intake, patients with EVE should be carefully monitored, especially for infections and stomatitis.
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Affiliation(s)
| | - Adam Strzelczyk
- Epilepsy Center Frankfurt Rhine-Main, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Andrea Nemecek
- Berlin-Brandenburg Epilepsy Center, Charité, Berlin, Germany
| | | | - Frank Bösebeck
- Agaplesion Diakonieklinikum Rotenburg Epilepsy Center, Rotenburg, Germany
| | | | - Hajo Hamer
- Erlangen Epilepsy Center, Erlangen University Hospital, Erlangen, Germany
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Esmat HA, Naseri MW. Giant renal pseudoaneurysm complicating angiomyolipoma in a patient with tuberous sclerosis complex: An unusual case report and review of the literature. Ann Med Surg (Lond) 2021; 62:131-134. [PMID: 33520209 PMCID: PMC7819805 DOI: 10.1016/j.amsu.2021.01.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/09/2021] [Accepted: 01/09/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction Angiomyolipomas (AMLs) are uncommon benign lesions, which are composed of dysmorphic blood vessels, adipose tissue, and smooth muscle components. They tend to bleed because of the hypervascularity and the presence of small aneurysms, leading to life-threatening complications. Presentation of case A 31-year-old female was presented to the emergency service of our hospital, complaining of left flank pain for 1 week followed by hematuria for one day. Radiologic imaging showed the features of a giant renal pseudoaneurysm. Superselective embolization was applied and she had an uneventful recovery. Discussion The blood vessels in AML are tortuous and thick-walled with the absence of supportive elastic tissue, which tend to the formation of the intralesional pseudoaneurysm. The risk of bleeding is higher with tumors larger than 4 cm, rapid tumor growth, and aneurysms larger than 0.5 cm. Early detection and treatment are essential for the prevention of bleeding and improving patient outcomes. Conclusion Giant pseudoaneurysm in a renal angiomyolipoma associated with tuberous sclerosis complex is a rare entity, often leading to potentially life-threatening bleeding. Selective angioembolization is recommended as firstline therapy for bleeding AML and is increasingly used as a preventive treatment for AML at risk of bleeding. However, a high incidence of the recurrence requires caution and a close longtime follow-up. Surgical intervention is indicated if the hemorrhage is not responsive to embolization or if there is suspicion of malignancy.
Renal pseudoaneurysm is a rare, but potentially life-threatening complication of tuberous sclerosis-related angiomyolipoma. Early detection is essential for the prevention of bleeding and improving the patient outcomes. Selective angioembolization is recommended as firstline therapy for bleeding angiomyolipoma. Surgical intervention is indicated if the hemorrhage is not responsive to embolization.
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Affiliation(s)
- Habib Ahmad Esmat
- Department of Radiology, Kabul University of Medical Sciences, Kabul, Afghanistan
| | - Mohammad Wali Naseri
- Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, Kabul University of Medical Sciences, Kabul, Afghanistan
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37
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Kingswood JC, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, Dahlin M, D'Amato L, Beaure d'Augères G, de Vries PJ, Ferreira JC, Feucht M, Fladrowski C, Hertzberg C, Jozwiak S, Lawson JA, Macaya A, Marques R, Nabbout R, O'Callaghan F, Qin J, Sander V, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Jansen AC, Sauter M. Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas. Front Neurol 2020; 11:972. [PMID: 33041968 PMCID: PMC7526256 DOI: 10.3389/fneur.2020.00972] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/24/2020] [Indexed: 12/18/2022] Open
Abstract
Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects (n = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients (p < 0.0001). Rates of angiomyolipomas >3 cm (p = 0.0119), growing lesions (p = 0.0439), and interventions for angiomyolipomas (p = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with TSC1 mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with TSC1 and TSC2 mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.
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Affiliation(s)
- J Chris Kingswood
- Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St Georges University of London, London, United Kingdom
| | - Elena Belousova
- Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Mirjana P Benedik
- Child Neurology Department, SPS Pediatrična Klinika, Ljubljana, Slovenia
| | - Tom Carter
- TSA Tuberous Sclerosis Association, Nottingham, United Kingdom
| | - Vincent Cottin
- Hôpital Louis Pradel, Claude Bernard University Lyon 1, Lyon, France
| | - Paolo Curatolo
- Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University Hospital, Rome, Italy
| | - Maria Dahlin
- Neuropediatric Department, Astrid Lindgren Children's Hospital, Stockholm, Sweden
| | | | | | - Petrus J de Vries
- Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa
| | - José C Ferreira
- Neurology Department, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal
| | - Martha Feucht
- Medical University of Vienna, Universitätsklinik für Kinder-und Jugendheilkunde, Affiliated Partner of the ERN EpiCARE, Vienna, Austria
| | - Carla Fladrowski
- Associazione Sclerosi Tuberosa ONLUS, Milan, Italy.,European Tuberous Sclerosis Complex Association, Dattein, Germany
| | - Christoph Hertzberg
- Zentrum für Neuropädiatrie und Sozialpädiatrie, Vivantes-Klinikum Neukölln, Berlin, Germany
| | - Sergiusz Jozwiak
- Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.,Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland
| | - John A Lawson
- The Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Alfons Macaya
- Pediatric Neurology Section, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Ruben Marques
- Novartis Farma S.p.A., Origgio, Italy.,Institute of Biomedicine (IBIOMED), University of Leon, León, Spain
| | - Rima Nabbout
- Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France
| | - Finbar O'Callaghan
- Institute of Child Health, University College London, London, United Kingdom
| | - Jiong Qin
- Department of Pediatrics, Peking University People's Hospital (PKUPH), Beijing, China
| | - Valentin Sander
- Department of Neurology and Rehabilitation, Tallinn Children Hospital, Tallinn, Estonia
| | - Seema Shah
- Novartis Healthcare Pvt. Ltd., Hyderabad, India
| | - Yukitoshi Takahashi
- National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
| | - Renaud Touraine
- Department of Genetics, CHU-Hôpital Nord, Saint-Étienne, France
| | - Sotiris Youroukos
- First Department of Paediatrics, Athens University, St. Sophia Children's Hospital, Athens, Greece
| | - Bernard Zonnenberg
- Department of Internal Medicine, University Medical Center, Utrecht, Netherlands
| | - Anna C Jansen
- Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel VUB, Brussels, Belgium
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Gimpel C, Bergmann C, Brinkert F, Cetiner M, Gembruch U, Haffner D, Kemper M, König J, Liebau M, Maier RF, Oh J, Pape L, Riechardt S, Rolle U, Rossi R, Stegmann J, Vester U, Kaisenberg CV, Weber S, Schaefer F. [Kidney Cysts and Cystic Nephropathies in Children - A Consensus Guideline by 10 German Medical Societies]. KLINISCHE PADIATRIE 2020; 232:228-248. [PMID: 32659844 DOI: 10.1055/a-1179-0728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation.
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Affiliation(s)
- Charlotte Gimpel
- Department of Internal Medicine IV, Medical Center - University of Freiburg, Freiburg
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau
| | - Carsten Bergmann
- Department of Internal Medicine IV, Medical Center - University of Freiburg, Freiburg
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau
- Medizinische Genetik Mainz, Limbach Genetics, Mainz
| | - Florian Brinkert
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Metin Cetiner
- Department of Pediatrics II, University Hospital Essen, Essen
| | - Ulrich Gembruch
- Department of Obstetrics and Prenatal Medicine, University Hospital of Bonn, Bonn
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover
| | - Markus Kemper
- Department of Pediatrics, Asklepios Kliniken Hamburg GmbH, Asklepios Klinik Nord, Standort Heidberg, Hamburg
| | - Jens König
- Department of General Pediatrics, University Children's Hospital Münster, Münster
| | - Max Liebau
- Department of Pediatrics, University Hospital Cologne, Cologne
- Center for Molecular Medicine, University of Cologne, Cologne
| | - Rolf Felix Maier
- Department of Pediatrics, University Hospital of Giessen and Marburg, Campus Marburg, Marburg
| | - Jun Oh
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Lars Pape
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover
| | - Silke Riechardt
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Udo Rolle
- Department of Pediatric Surgery, Hospital of the Goethe University Frankfurt, Frankfurt am Main
| | - Rainer Rossi
- Department of Pediatrics, Vivantes Klinikum Neukölln, Berlin
| | - Joachim Stegmann
- Department of Radiology, Catholic Children's Hospital Wilhelmstift, Hamburg
| | - Udo Vester
- Department of Pediatrics, HELIOS Hospital Duisburg, Duisburg
| | - Constantin von Kaisenberg
- Department of Obstetrics and Gynaecology, Center for Perinatal Medicine, Hannover Medical School, Hannover
| | - Stefanie Weber
- Department of Pediatrics, University Hospital of Giessen and Marburg, Campus Marburg, Marburg
| | - Franz Schaefer
- Center for Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology, University Hospital Heidelberg, Heidelberg
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Abstract
Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors, and seizures. TSC can manifest in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts, and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.
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40
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Pelizzo G, Vallone MG, Milazzo M, Rosone G, Amoroso S, Pavone G, D'Alessandro MM, Unti E, Calcaterra V. Renal angiomyolipomatosis and bleeding aneurysms in a tuberous sclerosis context: selective artery embolization in a girl with end-stage renal failure. Pediatr Rep 2020; 12:8352. [PMID: 32922707 PMCID: PMC7461646 DOI: 10.4081/pr.2020.8352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/05/2020] [Indexed: 11/30/2022] Open
Abstract
Recent developments in endovascular radiological techniques and devices have rendered embolization a major therapeutic option prior to surgery in many renal vascular or neoplastic diseases. A 19-yearold female patient, with a diagnosis of tuberous sclerosis complex (TSC) in childhood, was admitted with severe anemia. Polycystic kidney disease in end-stage renal failure appeared four years before and the patient has been undergoing peritoneal dialysis. The patient's medical history also included bilateral renal angiomyolipomas (AMLs). One year earlier, a unilateral endovascular embolization was performed to repair a bleeding aneurysm at the right renal upper pole. A second bilateral ruptured renal aneurysm was diagnosed at admission. To continue with peritoneal dialysis and prevent intrarenal hemorrhage and intraperitonal bleeding, an urgent bilateral renal AE was performed. Two months later she underwent a bilateral retroperitoneal nephrectomy. The posterior surgical approach, preserved the peritoneal surface area and adequate conditions to continue dialysis. At histology, bilateral AMLs were confirmed and a renal cell carcinoma of the right kidney was concurrently discovered. She undergoes continuous peritoneal dialysis. Urgent selective renal AE represents a feasible treatment for bilateral AML bleeding. It is safe and feasible before performing nephrectomy in patients with end-stage renal failure.
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Affiliation(s)
- Gloria Pelizzo
- Department of Biomedical and Clinical Science "L Sacco", University of Milan, Department of Pediatric Surgery, Children's Hospital V. Buzzi", Milan
| | - Mario Giuseppe Vallone
- Operative Unit of Vascular Radiology and Endovascular Therapy, ARNAS Civico-Di Cristina-Benfratelli, Palermo
| | - Mario Milazzo
- Pediatric Unit, ARNAS Civico-Di Cristina-Benfratelli, Palermo
| | - Gregorio Rosone
- Pediatric Unit, ARNAS Civico-Di Cristina-Benfratelli, Palermo
| | | | - Giovanni Pavone
- Pediatric Nephrology Unit, ARNAS Civico-Di Cristina-Benfratelli, Palermo
| | | | - Elettra Unti
- Pathology Unit, ARNAS Civico-Di Cristina-Benfratelli, Palermo
| | - Valeria Calcaterra
- Pediatrics and Adolescents Unit, Department of Internal Medicine University of Pavia; Children's Hospital "Vittore Buzzi", Milano, Italy
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Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant 2020; 34:1000-1008. [PMID: 30053159 PMCID: PMC6545468 DOI: 10.1093/ndt/gfy132] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Indexed: 02/06/2023] Open
Abstract
Background A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. Methods The long-term effects of EVE on renal function (∼4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5 mg/m2/day, with adjustment to achieve target trough levels of 5–15 ng/mL in EXIST-1 and at 10 mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3 months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88 mL/min/1.73 m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. Conclusions The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients. ClinicalTrials.gov identifiers NCT00789828 and NCT00790400
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Affiliation(s)
- John J Bissler
- St. Jude Children's Research Hospital and Le Bonheur Children's Hospital, Memphis, TN, USA
| | | | - Matthias Sauter
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - David N Franz
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | | | | | - Elena Belousova
- Moscow Research and Clinical Institute of Pediatrics, Moscow, Russian Federation
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From tuberous sclerosis complex to end stage renal disease: who are these patients? J Nephrol 2020; 34:607-615. [PMID: 32130718 DOI: 10.1007/s40620-020-00714-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 02/15/2020] [Indexed: 10/24/2022]
Abstract
In patients with tuberous sclerosis complex (TSC), renal complications are not limited to bleeding angiomyolipoma (AML); although rare, end-stage renal disease (ESRD) may occur. New treatments (e.g., mammalian target of rapamycin (m-Tor) inhibitors) for AML might influence the epidemiology of ESRD in patients with TSC. In France, 99 patients with TSC from the Renal Epidemiology and Information Network (REIN) registry and having undergone renal replacement therapy (RRT) between 2002 and 2016 were included in the present study. Additional data were collected from the patients' medical charts. The mean ± standard deviation age at RRT initiation was 48.4 ± 16.4 and 73.8% had a neurologic impairment. Fifty-four patients underwent kidney transplantation after an average of 23 ± 12.3 months on dialysis. Among the 61 patients with additional data the most common renal lesion was AML: 26.2% of the patients had isolated AML, and 26.2% had AML and renal cysts, 65.6% of patients had undergone nephrectomy, and 16.4% had undergone at least one embolization. None of the patients had been treated with an m-Tor inhibitor before dialysis. The graft survival rate was 92.5% at 5 years and 70.2% at 10 years. The present cohort study is the first to have assessed TSC patients on RRT from a national registry. Nephrectomy or embolization due to AML was the leading cause of ESRD in our cohort. By reducing the size of the AML, m-tor inhibitors might lower the risk of complications and thus reduce the number of patients with TSC requiring RRT.
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Ariceta G, Buj MJ, Furlano M, Martínez V, Matamala A, Morales M, Robles NR, Sans L, Villacampa F, Torra R. Recommendations for the management of renal involvement in the tuberous sclerosis complex. Nefrologia 2020; 40:142-151. [PMID: 31722796 DOI: 10.1016/j.nefroe.2020.03.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/04/2019] [Accepted: 07/15/2019] [Indexed: 02/07/2025] Open
Abstract
Tuberous sclerosis complex (TSC) is a rare, hereditary, multisystemic disease with a broad phenotypic spectrum. Its management requires the collaboration of multiple specialists. Just as in the paediatric age, the paediatric neurologist takes on special importance; in adulthood, renal involvement is the cause of the greatest morbidity and mortality. There are several recommendations on the general management of patients with TSC but none that focuses on renal involvement. These recommendations respond to the need to provide guidelines to facilitate a better knowledge and diagnostic-therapeutic management of the renal involvement of TSC through a rational use of complementary tests and the correct use of available treatments. Their elaboration has been based on consensus within the hereditary renal diseases working group of the SEN/REDINREN (Spanish Society of Nephrology/Kidney Research Network). It has also counted on the participation of non-nephrologist specialists in TSC in order to expand the vision of the disease.
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Affiliation(s)
- Gema Ariceta
- Servicio de Nefrología Pediátrica, Hospital Valle Hebrón, REDINREN, Barcelona, España
| | - María José Buj
- Servicio de Radiología, Hospital 12 de Octubre, Madrid, España
| | - Mónica Furlano
- Enfermedades Renales Hereditarias, Servicio de Nefrología, Fundació Puigvert, IIB Sant Pau, Universitat Autónoma de Barcelona, REDINREN, Barcelona, España
| | - Víctor Martínez
- Servicio de Nefrología, Hospital Virgen de la Arrixaca, Murcia, España
| | - Anna Matamala
- Departamento de Enfermería, Fundació Puigvert, Barcelona, España
| | | | | | - Laia Sans
- Servicio de Nefrología, Hospital del Mar, REDINREN, Barcelona, España
| | - Felipe Villacampa
- Servicio de Urología, Clínica Universidad de Navarra, Madrid, España
| | - Roser Torra
- Enfermedades Renales Hereditarias, Servicio de Nefrología, Fundació Puigvert, IIB Sant Pau, Universitat Autónoma de Barcelona, REDINREN, Barcelona, España.
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Zöllner JP, Franz DN, Hertzberg C, Nabbout R, Rosenow F, Sauter M, Schubert-Bast S, Wiemer-Kruel A, Strzelczyk A. A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC). Orphanet J Rare Dis 2020; 15:23. [PMID: 31964424 PMCID: PMC6975094 DOI: 10.1186/s13023-019-1258-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 11/19/2019] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs. METHODS We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included. RESULTS We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years. CONCLUSIONS TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.
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Affiliation(s)
- Johann Philipp Zöllner
- Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany
- LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany
| | - David Neal Franz
- Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Christoph Hertzberg
- Zentrum für Sozialpädiatrie & Neuropädiatrie (DBZ), Vivantes Klinikum Neukölln, Berlin, Germany
| | - Rima Nabbout
- Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Imagine Institute UMR1136, Paris, France
| | - Felix Rosenow
- Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany
- LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany
| | | | - Susanne Schubert-Bast
- Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany
- LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany
- Department of Neuropediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany
| | | | - Adam Strzelczyk
- Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.
- LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany.
- Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany.
- Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe-University Frankfurt, Schleusenweg 2-16 (Haus 95), 60528, Frankfurt am Main, Germany.
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Kingswood JC, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, Dahlin M, D' Amato L, d'Augères GB, de Vries PJ, Ferreira JC, Feucht M, Fladrowski C, Hertzberg C, Jozwiak S, Lawson JA, Macaya A, Marques R, Nabbout R, O'Callaghan F, Qin J, Sander V, Sauter M, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Jansen AC. Renal angiomyolipoma in patients with tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increase disease Awareness. Nephrol Dial Transplant 2019; 34:502-508. [PMID: 29697822 PMCID: PMC6399480 DOI: 10.1093/ndt/gfy063] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 02/06/2018] [Indexed: 12/31/2022] Open
Abstract
Background Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life-threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC. Methods Patients of any age with a documented clinic visit for TSC within 12 months or who were newly diagnosed with TSC before participation in the registry were eligible. Data specific to renal angiomyolipoma included physical tumour characteristics (multiple, bilateral, lesion size and growing lesions), clinical signs and symptoms, and management. The effects of age, gender and genotype on the prevalence of renal angiomyolipoma were also evaluated. Results Renal angiomyolipoma was reported in 51.8% of patients at baseline, with higher frequency in female patients (57.8% versus 42.2%). The median age at diagnosis was 12 years. Prevalence of angiomyolipoma was higher in patients with TSC2 compared with TSC1 mutations (59.2% versus 33.3%, P < 0.01). Of the 1031 patients with angiomyolipoma at baseline, multiple lesions were reported in 88.4% and bilateral in 83.9% of patients, while the size of angiomyolipoma was >3 cm in 34.3% of patients. Most patients were asymptomatic (82%). Frequently reported angiomyolipoma-related symptoms included bleeding, pain, elevated blood pressure and impaired renal function. Embolization and mammalian target of rapamycin inhibitors were the two most common treatment modalities. Conclusions The TOSCA registry highlights the burden of renal angiomyolipoma in patients with TSC and shows that renal manifestations are initially asymptomatic and are influenced by gender and genotype. Furthermore, the occurrence of significant problems from angiomyolipoma in a minority of younger patients suggests that surveillance should begin in infancy or at initial diagnosis.
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Affiliation(s)
| | - Elena Belousova
- Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russian Federation
| | | | - Tom Carter
- TSA Tuberous Sclerosis Association, Nottingham, UK
| | - Vincent Cottin
- Hôpital Louis Pradel, Claude Bernard University Lyon 1, Lyon, France
| | - Paolo Curatolo
- Department of Neurosciences, Child Neurology and Psychiatry Unit, Tor Vergata University Hospital, Rome, Italy
| | - Maria Dahlin
- Department of Pediatric Neurology, Karolinska University Hospital, Stockholm, Sweden
| | | | | | - Petrus J de Vries
- Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa
| | - José C Ferreira
- Department of Neurology, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal
| | - Martha Feucht
- Department of Paediatrics, Universitätsklinik für Kinder-und Jugendheilkunde, Vienna, Austria
| | - Carla Fladrowski
- Associazione Sclerosi Tuberosa ONLUS, Milan, Italy.,European Tuberous Sclerosis Complex Association, In den Birken, Dattein, Germany
| | - Christoph Hertzberg
- Chefarzt des Zentrums für Sozial- und Neuropädiatrie, Vivantes-Klinikum Neukölln, Berlin, Germany
| | - Sergiusz Jozwiak
- Department of Child Neurology, Warsaw Medical University, Warsaw, Poland.,Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland
| | - John A Lawson
- The Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children's Hospital, Randwick, Australia
| | - Alfons Macaya
- Sección de Neurología Pediátrica, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Ruben Marques
- Novartis Farma S.p.A., Origgio, Italy.,The Institute of Biomedicine University of Leon, Spain
| | - Rima Nabbout
- Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France
| | | | - Jiong Qin
- Department of Pediatrics, Peking University People's Hospital (PKUPH), Beijing, China
| | - Valentin Sander
- Department of Neurology, Tallinn Children Hospital, Tallinn, Estonia
| | - Matthias Sauter
- Abteilung für Hygiene und Infektiologie, Klinikverbund Kempten-Oberallgäu gGmbH, Kempten, Germany
| | - Seema Shah
- Novartis Healthcare Pvt. Ltd, Hyderabad, Telangana, India
| | - Yukitoshi Takahashi
- National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama Aoi-ku Shizuoka, Japan
| | - Renaud Touraine
- Department of Genetics, CHU-Hôpital Nord, Saint Etienne, France
| | - Sotiris Youroukos
- First Department of Paediatrics, Athens University Medical School, St Sophia Children's Hospital, Athens, Greece
| | - Bernard Zonnenberg
- Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands
| | - Anna C Jansen
- Department of Pediatrics, Pediatric Neurology Unit, UZ Brussel VUB, Brussels, Belgium
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46
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Vergeer M, de Ranitz‐Greven WL, Neary MP, Ionescu‐Ittu R, Emond B, Sheng Duh M, Jansen F, Zonnenberg BA. Epilepsy, impaired functioning, and quality of life in patients with tuberous sclerosis complex. Epilepsia Open 2019; 4:581-592. [PMID: 31819914 PMCID: PMC6885664 DOI: 10.1002/epi4.12365] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 08/16/2019] [Accepted: 10/02/2019] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE To estimate health-related quality of life (HRQoL) in patients with tuberous sclerosis complex (TSC) and associated manifestations and to identify potential factors associated with HRQoL in this population of patients. METHODS We performed a retrospective chart review of adults with TSC who attended the outpatient clinic of the University Medical Center Utrecht in the Netherlands from 1990 to 2015 (N = 363; on average 33.6 years of follow-up). HRQoL data were assessed in 2012 using the Health Utility Index version 3 (HUI-3) questionnaire completed by patients or caregivers (N = 214 with HUI score and ≥1 TSC manifestation, including renal angiomyolipomas [rAMLs], subependymal giant cell astrocytoma [SEGA], or epilepsy). RESULTS Of 214 patients in the study sample, 171 had TSC-associated epilepsy (with or without rAML/SEGA), 37 had TSC and rAML (without epilepsy or SEGA), and 6 had other combinations of manifestations. The median HUI score for the 214 patients with ≥1 TSC manifestation was 0.51 (-0.371 to 1 scale, 1 = perfect health, 0 = death, <0 = worse than death). Among all components used to build the overall HUI score, the cognition component had the lowest score (mean = 0.47; 0-1 scale). Patients with TSC-epilepsy had significantly lower overall HUI than patients with TSC and rAML only (median HUI = 0.31 vs 0.95, P < .05), especially those who were in refractory state for prolonged periods of time (median HUI = -0.11 among patients with seizures during the entire duration of their follow-up time). In multivariate analyses, severe impairment of daily functioning was the strongest predictor of HRQoL decrement (adjusted HUI difference between patients with severe vs. no impairment = -0.55, P < .05). SIGNIFICANCE This study showed that TSC-related epilepsy is associated with lower HUI, especially for patients who have refractory seizures for prolonged periods of time. Early and effective interventions to control or reduce seizures and preserve patients' cognitive functions may help to improve patients' quality of life.
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Affiliation(s)
| | | | | | | | | | | | - Floor Jansen
- University Medical Center UtrechtUtrechtNetherlands
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Ariceta G, Buj MJ, Furlano M, Martínez V, Matamala A, Morales M, Robles NR, Sans L, Villacampa F, Torra R. Recommendations for the management of renal involvement in the tuberous sclerosis complex. Nefrologia 2019; 40:142-151. [PMID: 31722796 DOI: 10.1016/j.nefro.2019.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/04/2019] [Accepted: 07/15/2019] [Indexed: 12/01/2022] Open
Abstract
Tuberous sclerosis complex (TSC) is a rare, hereditary, multisystemic disease with a broad phenotypic spectrum. Its management requires the collaboration of multiple specialists. Just as in the paediatric age, the paediatric neurologist takes on special importance; in adulthood, renal involvement is the cause of the greatest morbidity and mortality. There are several recommendations on the general management of patients with TSC but none that focuses on renal involvement. These recommendations respond to the need to provide guidelines to facilitate a better knowledge and diagnostic-therapeutic management of the renal involvement of TSC through a rational use of complementary tests and the correct use of available treatments. Their elaboration has been based on consensus within the hereditary renal diseases working group of the SEN/REDINREN (Spanish Society of Nephrology/Kidney Research Network). It has also counted on the participation of non-nephrologist specialists in TSC in order to expand the vision of the disease.
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Affiliation(s)
- Gema Ariceta
- Servicio de Nefrología Pediátrica, Hospital Valle Hebrón, REDINREN, Barcelona, España
| | - María José Buj
- Servicio de Radiología, Hospital 12 de Octubre, Madrid, España
| | - Mónica Furlano
- Enfermedades Renales Hereditarias, Servicio de Nefrología, Fundació Puigvert, IIB Sant Pau, Universitat Autónoma de Barcelona, REDINREN, Barcelona, España
| | - Víctor Martínez
- Servicio de Nefrología, Hospital Virgen de la Arrixaca, Murcia, España
| | - Anna Matamala
- Departamento de Enfermería, Fundació Puigvert, Barcelona, España
| | | | | | - Laia Sans
- Servicio de Nefrología, Hospital del Mar, REDINREN, Barcelona, España
| | - Felipe Villacampa
- Servicio de Urología, Clínica Universidad de Navarra, Madrid, España
| | - Roser Torra
- Enfermedades Renales Hereditarias, Servicio de Nefrología, Fundació Puigvert, IIB Sant Pau, Universitat Autónoma de Barcelona, REDINREN, Barcelona, España.
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Anis O, Rimon U, Ramon J, Khaitovich B, Zilberman DE, Portnoy O, Dotan ZA. Selective Arterial Embolization for Large or Symptomatic Renal Angiomyolipoma: 10 Years of Follow-up. Urology 2019; 135:82-87. [PMID: 31618658 DOI: 10.1016/j.urology.2019.09.035] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 09/25/2019] [Accepted: 09/29/2019] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To assess long-term outcome after selective arterial embolization (SAE) as first-line treatment for large or symptomatic AML. DESIGN, SETTING, AND PARTICIPANTS Data from a prospectively maintained database on 71 patients who underwent SAE for large or symptomatic AML were reviewed. Patients with sporadic and tuberous-sclerosis-complex (TSC) were included. OUTCOME MEASUREMENTS The main endpoints were re-embolization rates, occurrence of clinical events related to AML, size of AML, and renal function. RESULTS Thirteen (19.1%) patients reported at least 1 major clinical event. Major complications affected 2 patients (2.9%), both ending in complete loss of renal unit function. Four renal units (5.9%) were eventually treated surgically. The re-embolization rate was 41.1%, with an average time from the initial to a repeat SAE of 2.18 years (range 0.31-10.65 years). The size of the tumor prior to SAE and after 5 and 10 years of follow-up were 8.9 cm (7-12), 6.5 cm (4-7.5), 7 cm (4-7.8), respectively [median (IQR)]. These results are translated to a size reduction of 27% in 10 years follow-up. Patients with TSC had larger tumors on long-term follow-up (77.8 vs 41.3 mm, P = .045). The long-term follow-up estimated average glomerular filtration rate was 81.97 (range 26-196). No patient needed renal replacement therapy, and disease-specific survival was 100%. CONCLUSIONS SAE is a safe treatment option for patients with symptomatic or large AML. It represents a minimally invasive intervention with good long-term outcome. SAE may be offered as first-line treatment in most cases, though, it is associated with high retreatment rates.
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Affiliation(s)
- Omer Anis
- Departments of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
| | - Uri Rimon
- Departments of Diagnostic Imaging, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Jacob Ramon
- Departments of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Boris Khaitovich
- Departments of Diagnostic Imaging, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Dorit E Zilberman
- Departments of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Orith Portnoy
- Departments of Diagnostic Imaging, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Zohar A Dotan
- Departments of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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Champy CM, Campi R, Grande P, de la Taille A, Méjean A, Granger B, Bitker MO, Rouprêt M. How many surgically-treated angiomyolipomas are related to tuberous sclerosis complex? Insights from a retrospective multicenter study. MINERVA UROL NEFROL 2019; 72:200-206. [PMID: 31619031 DOI: 10.23736/s0393-2249.19.03522-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Patients with TSC - related renal angiomyolipoma (AML) are eligible for targeted therapy with mTOR inhibitors, avoiding the morbidity of interventional management. Despite clinical criteria for TSC diagnosis have been defined, their use in routine clinical practice is likely suboptimal, leading to potential misclassification of TSC-related AML. The study aims to assess the proportion and characteristics of surgically-treated patients with putative sporadic AML that would have been re-classified as TSC-related. METHODS We retrospectively reviewed a prospectively collected multi-institutional database to select patients with suspected TSC-related AML among those undergoing surgery at three referral Centers over 11-years (2005-2015). Possible diagnosis of TSC was defined according to the 2012 International Tuberous Sclerosis Complex Consensus (ITSCC) criteria. The proportion and characteristics of patients with possible TSC-related AML (as compared to those of patients with sporadic AML) were considered the main study endpoints. RESULTS Overall, 132 patients were included. Of these, 10 (7.6%) were considered TSC-related. Most patients (84%) were female. Patients with TSC-related AML were likely to be younger (median age 53 vs. 56 years, P=0.29), symptomatic at diagnosis (70% vs. 21%, P=0.002), with slightly worse preoperative physical status (median ASA score 2 vs. 1, P=0.001) and bilateral disease (30% vs. 7.4%, P=0.04) as compared to patients with sporadic AML. Anatomic complexity and tumor size were also higher among TSC-related AMLs. CONCLUSIONS A non-negligible proportion of surgically-treated, putative sporadic AMLs were reclassified as potentially hereditary (TSC-related). As TSC patients may be treated with targeted therapies, our findings may increase urologists' awareness of TSC-related AML and prompt the design of future studies evaluating targeted diagnostic pathways for these patients.
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Affiliation(s)
- Cécile M Champy
- Sorbonne Université, GRC n°5, ONCOTYPE-URO, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
| | - Riccardo Campi
- Sorbonne Université, GRC n°5, ONCOTYPE-URO, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.,Department of Urology, Careggi Hospital, University of Florence, Florence, Italy
| | - Pietro Grande
- Sorbonne Université, GRC n°5, ONCOTYPE-URO, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.,Department of Obstetrical and Gynecological Sciences and Urologic Sciences, 'Sapienza' University, Rome, Italy
| | - Alexandre de la Taille
- Department of Urology, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP) CHU Mondor, Faculté de Médecine, Créteil, France
| | - Arnaud Méjean
- Department of Urology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France
| | - Benjamin Granger
- Department of Biostatistics, Groupe Hospitalo-Universitaire EST, Pitié-Salpétrière Hospital, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
| | - Marc-Olivier Bitker
- Sorbonne Université, GRC n°5, ONCOTYPE-URO, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
| | - Morgan Rouprêt
- Sorbonne Université, GRC n°5, ONCOTYPE-URO, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France -
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Sheu TC, Holt D, Moole V, Barth D, Nolte R, Swischuk J. Renal artery bypass including aortic graft for renovascular hypertension. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2019. [DOI: 10.1016/j.epsc.2019.101295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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