Wednesday, July 12, 2017

Renal disease in tuberous sclerosis 2

“Admittedly, my practice is limited to pediatrics. Of the many (and I do mean many) patients I have seen with tuberous sclerosis since 1984, none to date has had a symptomatic angiomyolipoma… I have never had a patient who underwent surgical intervention for tuberous sclerosis related renal disease nor at present do I know of any such patient treated by my colleagues locally, and I am a pretty nosy guy.”

Wataya-Kaneda M, Uemura M, Fujita K, Hirata H, Osuga K, Kagitani-Shimono K, Nonomura N; Tuberous Sclerosis Complex Board of Osaka University Hospital. Tuberous sclerosis complex: Recent advances in manifestations and therapy. Int J Urol. 2017 Jul 1. doi: 10.1111/iju.13390. [Epub ahead of print]

Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, "a cross-sectional medical examination system," a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex-associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex.

From the article

Angiomyolipomas, which develop most commonly in the kidney, but can occur in other organs, are benign tumors composed of vascular, smooth muscle and adipose tissue.  Multiple bilateral renal angiomyolipomas are a feature relatively specific to TSC. Fat-containing angiomyolipomas were observed in 80% of TSC patients, and fat-poor lesions, which are uncommon and occur in <0.1% of the general population are also common in patients with TSC. However, if there is doubt about malignancy and/or lesions are growing faster than 0.5 cm per year, a needle biopsy or an open biopsy can be considered.

Renal angiomyolipomas appear by 10.5 years-of-age, and increase in size and number in the late teens and early 20s. Sometimes, they increase rapidly within a short period. Although renal angiomyolipomas are often not clinically significant without symptoms and abnormal blood test values, they can grow to be quite large, particularly in women, and can cause serious issues with bleeding. The size of the aneurysm appears to be proportional to the risk of bleeding, and aneurysms larger than 5 mm are at high risk.

Although the size of an angiomyolipoma roughly correlates with the risk of hemorrhage, the risk has been more firmly linked to the presence of an aneurysm within the angiomyolipoma.  In the 2012 International TSC Consensus Conference for asymptomatic, growing angiomyolipomas measuring more than 3 cm in diameter, treatment with an mTORC1 inhibitor is the recommended first-line therapy. However, there is no evidence of any relationship between the risk of bleeding and the size in angiomyolipoma of 3 cm, which is an entry criteria for the EXIST-2 clinical trial. In Japan, growing asymptomatic angiomyolipomas larger than 4 cm in diameter and/or with an aneurysm larger than 5 mm in diameter are recommended for preventive transarterial embolization or treatment with an mTORC1 inhibitor. Embolization followed by corticosteroids is the first-line therapy for angiomyolipomas presenting with acute bleeding. As the renal function is usually normal, even in patients with bilateral large confluent angiomyolipomas, nephrectomy is to be avoided if possible.

Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES. Renal lesion growth in children with tuberous sclerosis complex. J Urol. 1998 Jul;160(1):141-5.

Renal lesions, including angiomyolipoma, renal cysts (simple and polycystic kidney disease) and renal cell carcinoma, develop in patients with tuberous sclerosis complex. While there is limited information that these lesions may grow in adults with tuberous sclerosis complex, the incidence, characterization and growth rate in children have not been reported. Also, the age at which these lesions first appear, thus providing insight into their natural history, is unknown. We present our data from a longitudinal renal surveillance study of children with tuberous sclerosis complex.
Since 1985 children with tuberous sclerosis complex at our hospital have undergone periodic renal imaging by ultrasonography or computerized tomography to monitor renal lesions. A total of 35 girls and 25 boys 1 to 18 years old have undergone at least 2 or more annual renal ultrasounds.
On initial evaluation 33 of 60 children (55%) (mean age 6.9 years) had an identifiable renal lesion, which increased to 48 of 60 (80%) at followup (mean age 10.5 years). Angiomyolipoma was the most frequent lesion (75%) followed by simple renal cysts (17%). Angiomyolipomas increased in size and/or number in 10 of 18 boys (56%) and 18 of 27 girls (66%). The largest growth rate in 1 year was from 0 to 4 cm. and from 5 to 9 cm. in diameter. The youngest patient demonstrated lesions at age 2 years. The average age at which a normal ultrasound became abnormal was 7.2 years. While a total of 27 patients had a normal ultrasound on entering the study, lesions had developed in 15 at followup (11 with angiomyolipomas, 4 with cysts). Five patients had cysts that had disappeared at followup. A 7-year-old boy had a 9 cm. renal cell carcinoma removed. One patient has renal lesions characteristic of autosomal dominant polycystic kidney disease.
Renal involvement in patients with tuberous sclerosis complex begins in infancy, and angiomyolipoma is the most common lesion (75%). Angiomyolipomas are more likely to grow than remain stable, although the rate of growth varies. Simple renal cysts may appear or disappear with time but angiomyolipomas do not disappear. An initially normal renal ultrasound does not rule out future development of lesions. Periodic surveillance is indicated in children with tuberous sclerosis complex.


  1. At the time of diagnosis, abdominal imaging should be obtained regardless of age. As for brain, MRI is the preferred modality for evaluation of angiomyolipomata because many can be fat-poor and hence missed when abdominal CT or US are performed. MRI of the abdomen may be combined in the same session as MRI of the brain, thereby limiting the need for multiple sessions of anesthesia if anesthesia is needed for successful MRI. MRI of the abdomen may also reveal aortic aneurysms or extrarenal hamartomas of the liver, pancreas, and other abdominal organs that also can occur in individuals with TSC. In addition to imaging, accurate blood pressure assessment is important because of increased risk of secondary hypertension. To assess renal function at time of diagnosis, blood tests to determine glomerular filtration rate (GFR) using creatinine equations for adults or children. Alternatively, measurement of serum cystatin C concentration can be used to evaluate GFR.(Category 1)…

    For asymptomatic, growing angiomyolipoma measuring larger than 3 cm in diameter, treatment with an mTOR inhibitor is currently recommended as the most effective first-line therapy in the short term. The demonstrated tolerability so far to date is far preferable to the renal damage caused by angiomyolipoma progression as well as surgical and embolitic/ablative therapies, though studies are still needed to confirm long-term benefits and safety. (Category 1)

    Annual clinical assessment of renal function and hypertension is required. Blood pressure control is also critical, so accurate measurement of blood pressure for patients is crucial, using age-specific criteria for children. Patients with hypertension should be treated with an inhibitor of the renin-aldosterone-angiotensin system as first line therapy, but avoiding an angiotensin-converting enzyme inhibitor in those treated with an mTOR inhibitor. (Category 1)

    Imaging to diagnose polycystic disease, renal cell carcinoma or other tumors, and changes in angiomyolipoma should also be performed. MRI, often obtainable at the same time as brain surveillance imaging, is the preferred imaging modality, but if MRI is not available, CT or US can still provide useful information. Selective embolization followed by corticosteroids, kidney-sparing resection, or ablative therapy for exophytic lesions are acceptable second-line therapy for asymptomatic angiomyolipomata. For acute hemorrhage, embolization followed by corticosteroids is more appropriate. Nephrectomy is to be avoided because of the high incidence of complications and increased risk of future renal insufficiency, end-stage renal failure, and the poor prognosis that results from chronic kidney disease. Fat-poor angiomyolipomata are not uncommon in patients with TSC, but if there is doubt and lesions are growing faster than 0.5 cm per year,48 a needle biopsy using a sheath technique or an open biopsy may be considered. (Category 2A)

    Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct;49(4):255-65.

  2. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc. 1991 Aug;66(8):792-6.

    Of the 355 patients with tuberous sclerosis complex (TSC) examined at the Mayo Clinic, 49 had died (9 of causes other than TSC). We attempted to determine what pattern of organ involvement occurred most often in the 40 patients who died of TSC. One baby died of cardiac failure due to cardiac rhabdomyomas, and one child died of rupture of an aneurysm of the thoracic aorta. Eleven patients died of renal disease, which was the commonest cause of death. Ten patients died as a result of brain tumors, and four patients (who were 40 years of age or older) died of lymphangiomyomatosis of the lung. Thirteen patients with severe mental handicaps died of either status epilepticus or bronchopneumonia; in all but one of these patients, the only source of information was the death certificate. Survival curves show a decreased survival for patients with TSC in comparison with that for the general population. Patients with TSC need lifelong follow-up for early detection of potentially life-threatening complications.