mTOR inhibition is likely to transform management of tuberous sclerosis complex and the results of landmark trials are being studied to see if the encouraging reductions in tumour size translate into improved outcomes for patients in the long term
Partha Das MSc MBBS MRCP
John Chris Kingswood MBBS FRCP
Sussex Kidney Unit, Royal Sussex County Hospital, Brighton, UK
Disclaimer: Funded by Novartis. Novartis had no editorial input into the writing of this article apart from checking for factual accuracies
Tuberous sclerosis complex (TSC) is an autosomal dominant condition characterised by the proliferation of benign tumours affecting multiple organ sites. The last 20 years have seen significant advances in the investigation and management of the condition including the widespread use of more sensitive imaging techniques and the advent of drugs that inhibit the mammalian target of rapamycin (mTOR) pathway for effective pharmacological management. This article reviews the background, pathophysiology and diagnosis of the condition but focuses primarily on the management of the renal manifestations of TSC.
Renal disease is important and can manifest in several ways, from hypertension and chronic kidney disease (CKD) through to haemorrhage from renal parenchymal tumours but warrants particular attention because of its strong association with an increased risk of death in TSC patients.1
The earliest description of the condition is ascribed to a figure in an atlas of skin diseases published in 1835 by the French dermatologist Pierre Francois Olive Rayer2 demonstrating vascular papulous growths around the nose and mouth of a woman. The rash would later be eponymised as Pringle’s adenoma sebaceum after the Scottish dermatologist John James Pringle and become common parlance for the facial rash of TSC. Desire-Magloire Bourneville, a French neurologist, noted raised, firm sclerotic cerebral gyri which he described as, “tuberous sclerosis of the cerebral convolutions” at post-mortem examination of a teenage girl with learning difficulties, seizures and a facial rash.
Incidentally her kidneys also demonstrated white hard sclerotic masses. It was only in the 20th century that Heinrich Vogt associated the triad of learning disabilities, epilepsy and adenoma sebaceum with the skin and cerebral features of the tuberous sclerosis complex described by Bourneville. Current epidemiological data suggest that 50% of patients have all three features3; although the prevalence and severity is diminishing with better earlier treatment of infantile spasms.4,5 Advances in imaging and molecular biology through the end of the 20th century and start of the 21st century have lead to significant advances in the diagnosis and understanding of the pathogenesis of the condition and most recently have allowed therapeutic treatments to be utilised.
TSC has no gender predilection and presentation can be at any age, although the pathological features become more apparent at different ages depending on the organ system involved.6 Similarly there is no particular ethnic preference. The most common causes of death of TSC patients are from the neurological and renal complications. The birth incidence of TSC in Europe is approximately 1 in 5800 with a prevalence of 8.8 per 100,000.7,8 There are many confounding factors affecting the accuracy of these statistics including under-recognition of some phenotypes due to presentation variability, and perhaps social stigma associated with the diagnosis. This is important to recognise as lack of basic epidemiological data can have a negative impact on service planning and organisation in a region. Improved data collection in the form of a registry might help overcome this in the future. The recently multinational TOSCA registry dataset, which now has 2201 recruits, will better define the natural history, rare complications and effects of treatment in TSC9; it is a longitudinal observational study.
Two gene loci have been identified as important for the development of the TSC phenotype through linkage analysis and subsequent cloning.10 These have been designated TSC1, located on chromosome 9, and TSC2, found on chromosome 16. There is a high spontaneous mutation rate and only 20–30% of cases are familial.6,10 This lack of family history can make clinical diagnosis difficult in more subtle cases and contributes to the inaccuracies in epidemiological data.
TSC1 encodes a protein called hamartin and TSC2 encodes the protein tuberin. The full physiological functions of each of these proteins have not been fully delineated but they have a major role in controlling cell growth.
Both proteins combine to form a complex that inactivates a GTPase called rheb (Ras homologue enhanced in brain). In its active GTP-bound state, rheb acts on the mTOR, which promotes cell growth and protein synthesis through protein S6 kinase. It has been postulated that mutations in either the hamartin or tuberin genes lead to unchecked mTOR activity through maintenance of rheb in its GTP-bound state, which then lead to unregulated cell proliferation. It is this dysregulation that is thought to lead to the formation of organ tumours in TSC which, in turn, cause maldevelopment of the brain and the growth of tumours.11
In addition to this, there is evidence that tumours in many organs of TSC patients (for example, kidney and lung) develop through a Knudsen ‘2-hit’ process. Within a single affected cell, the second copy of the gene is mutated before control of the mTOR pathway is lost completely, leading to tumours arising from that cell.12
TSC can affect several organ systems and manifest at various stages of development. The cortical tubers and cardiac tumours often develop during embryogenesis whereas skin manifestations occur in over 90% of patients at all ages.6 Despite this, some patients will not necessarily have any obvious clinical manifestations and this can make identification difficult unless specifically looked for during physical examination.
The spectrum of renal disease varies from cystic kidney disease (in 20%) to renal angiomyolipomas (AMLs; in 60–80% and have a risk of causing life-threatening haemorrhage), rarely other tumours (for example, renal cell carcinoma (2–3%)) or oncocytoma,13 CKD (with estimated glomerular filtration rate < 60ml/min, 40%),14 or end stage renal failure (5%) requiring renal replacement therapy. Like other organ manifestations, different kidney pathologies tend to develop at different ages with renal cysts occurring in early childhood whereas AMLs tend to be diagnosed in later childhood or early adolescence as they enlarge and are more easily visualised through imaging techniques. The incidence of kidney involvement has been suggested to be anywhere from half of all TSC patients to 90%. In one cohort, 55% of children at a mean age of 6.9 years had some form of renal abnormality on ultrasound imaging and at follow-up, 80% (mean age 10.5). It might be inferred that pathology begins in early age and progresses through life.15
Renal cysts can either behave as simple cysts or, in 5% of cases, take on a phenotype similar to polycystic kidney disease (PKD). Recent research has identified that patients with the PKD phenotype of TSC have a deletion across the tip of chromosome 16 affecting both TSC2 and the neighbouring PKD1 gene.16
Furthermore, episodes of acute kidney injury (AKI) from infection, volume depletion or the nephrotoxic effects of drugs used to treat non-renal symptoms of TSC (for example, anticonvulsants, non-steroidal anti-inflammatory drugs) may accelerate TSC-associated renal cystic disease, growth of AMLs or CKD.
Perhaps the most significant renal cause of morbidity and mortality in TSC is due to complications that arise from AMLs. These are derived from a family of tumours called perivascular epithelial cell tumours (PEComas). Cells within AMLs have melanocytic and smooth muscle precursors so will stain with the monoclonal antibody HMB45 and are deficient in either tuberin or hamartin.15 Estimates of rate of growth vary although observational data show that the fastest growth period is in childhood and adolescence with a slowing down in adulthood.17
As AMLs grow they may encroach on normal renal tissue, reducing kidney function and increasing the risk of chronic kidney disease. Furthermore larger AMLs develop aneurysms that can rupture and cause haemorrhage. The risk of AML-related haemorrhage is estimated at between 25% and 50%, with up to 20% presenting as emergencies with circulatory compromise. Balancing the benefits of pre-emptive treatment of AMLs to reduce progression of CKD or risk of haemorrhage with the risks of complications from any intervention presents a treatment conundrum; if the treatments used potentially destroy normal kidney tissue (for example, surgery or embolisation)18 and have a high recurrence rate,19 their long-term benefits are severely limited.20
Despite the high preponderance of renal AMLs in TSC, the incidence of malignant neoplastic lesions such as renal cell carcinoma is similar to the normal population (2–3%), but occurs at a younger age.
Non-parenchymal renal disease includes renin-mediated hypertension from PKD. There is also a predilection for nephrolithiasis, which is primarily related to the use of drug treatment for other TSC manifestations, for example, the anticonvulsant topiramate – inhibits carbonic anhydrase II and IV and decreases urinary citrate excretion. Furthermore, treatment with a ketogenic diet (for intractable epilepsy) leads to hypercalciuria and hypocitraturia increasing the risk of stone formation. The diet is also associated with decreased urine uric acid solubility from a low urine pH. Finally disrupted distal tubular function due to cystic disease can cause hypocitraturia.
Minimally invasive treatment includes extracorporeal shockwave lithotripsy, percutaneous nephrolithotomy and ureteroscopic stone removal. Because of the likelihood of bleeding, the latter most likely carries the lowest risk of complications but treatment options should be carefully assessed in a multi-disciplinary team setting.
Diagnosis of TSC
Because of the wide variety of phenotypes now identified, the classical descriptions of TSC are less relevant today. Efforts to standardise and improve diagnosis have been made through the development of consensus criteria21 (see Table 1).
Molecular genetic testing to identify mutations in TSC1 and TSC2 is becoming increasingly available. Although testing may not detect up to 15% of mutations, it can be useful in cases where diagnosis is uncertain or for prenatal diagnosis where the mutation has already been identified in the index case.
The growth of imaging techniques has been invaluable in visualising renal cysts and tumours but utility is largely dependent on resolution and inherent limitations of the various imaging modalities. Pathological studies have suggested that it is possible that all TSC patients have microscopic AMLs or cystic disease, which may not be apparent on any imaging modality. Ultrasound (US) is good at detecting the adipose component of AMLs but fat-poor lesions can also coexist in TSC so may be misdiagnosed. Computed tomography (CT) can delineate tissues and gives an opportunity to perform concomitant angiography but involves radiation exposure and an intravenous contrast load, which can cause AKI. This, in turn, may worsen underlying CKD. Magnetic resonance imaging (MRI) provides excellent detection and delineation of AMLs and can be added sequentially to brain imaging although sedation may be required. The 2012 TSC Consensus Conference has recommended abdominal MRI as the modality of choice where possible.22
General approaches to the management of renal manifestations of TSC have similarities to the care of the patient with CKD from other causes. Prevention of episodes of AKI includes ensuring adequate hydration during periods of intercurrent illness and prompt treatment of other common causes of AKI such as infection. Appropriate dosing of drugs for other symptoms of TSC to avoid nephrotoxic effects is also crucial. Where hypertension is present, blood pressure should be treated to target levels with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin 2 receptor blocker (ARB) as per local CKD guidelines23; except that in those taking an mTOR inhibitor caution is needed because angioedema may be more common when simultaneously treated with an ACEI.22 Again care should be taken to review the need for an ACEI/ARB during an episode of AKI. Finally, should nephrolithiasis be present, attention should be paid to maintaining hydration status. Distal tubular dysfunction causing hypocitraturia can be addressed with dietary citrate supplementation.
Interventional options for treatment of AMLs have previously included a variety of open and laparoscopic surgical methods. Surgery can be technically difficult and risks compromising residual kidney function further, even with ‘nephron-sparing’ techniques. Although there will be occasions when surgery is preferred, consensus guidelines at present suggest that radiological embolisation of individual AMLs is the standard of care to control active bleeding and to prevent bleeding from lesions with large aneurysms (>5mm).
As the understanding of the genetics and cellular biology of TSC has progressed, targets for potential drug treatments have become apparent. The mTOR inhibitor group of drugs currently show the greatest promise in a series of multi-centre trials, and pre-emptive treatment with an mTOR inhibitor is now the first treatment of choice; for AMLs > 3cm that are still growing.22
As described previously, hamartin and tuberin act through rheb to downregulate mTOR, which thereby acts as a brake to prevent cell proliferation. Although the genetic defects in hamartin and tuberin cannot be addressed at present, inhibiting mTOR directly can restore some of this molecular braking mechanism. mTOR inhibitors have been used in several other settings including immunosuppression for organ transplantation and it has been shown that AML burden can be reduced significantly through the use of the mTOR inhibitors sirolimus or everolimus.
Sirolimus (rapamycin) is capable of inducing regression of renal angiomyolipomas in animal models of TSC, and this effect appears to be enhanced by interferon-gamma, whose receptors are upregulated by overactivity of mTOR. Trials of sirolimus for renal AMLs in humans with TSC have suggested that sirolimus therapy can cause improvements in AML size when treated for up to 24 months.24–27 However, sirolimus studies have not progressed beyond Phase II and sirolimus does not have a license for treatment of TSC complications.
Everolimus is another mTOR inhibitor and has been the subject of two landmark TSC trials.
EXIST-128 was an international multicentre, double-blinded, placebo-controlled Phase III trial examining the efficacy and safety of everolimus in reducing the size of subependymal giant cell astrocytomas (SEGAs), which are common progressive brain tumours found in 10% of TSC patients and that continue to grow inexorably in half of affected patients.
The trial demonstrated efficacy of mTOR inhibition in stopping the growth of tumours in TSC and indeed the majority progressively reduced in size. A total of 38% of the patients (age 1–27 years) in EXIST-1 also had at least one renal AML 1cm in diameter or larger. All such AMLs were measured at follow-up as a secondary end-point.29 In those patients in the everolimus group (n=30), 100% of the AMLs remained stable or shrank compared with the 14 patients in the placebo arm where only one showed any shrinkage.27 Longer-term follow up has shown that there continues to be an acceptable side effect profile.30
EXIST-231 was a randomised double-blinded, placebo controlled Phase III trial investigating the efficacy of everolimus in reducing the size of AMLs associated with TSC and also a lung condition – sporadic lymphangioleiomyomatosis – compared with placebo. Inclusion criteria were patients aged 18 years or above, the presence of at least one AML with longest diameter >3cm and a diagnosis of TSC based on the consensus criteria or sporadic lymphangioleiomyomatosis on chest CT/biopsy.
The primary outcome measure was a composite measure set, a priori, as the proportion of patients with a confirmed AML response to treatment (defined as decrease in total volume of all AMLs >1cm of 50% by MRI or CT) in the absence of AML progression; that is, an increase in kidney volume of >20%, development of a new AML >1cm in diameter, or an AML-related renal bleed ≥grade 2. A number of secondary endpoints were also specified including time to AML progression, improvements in skin rash, neurocognition and safety. A total of 118 patients from 24 centres over 11 countries were recruited in a 2:1 ratio (everolimus arm 79 patients, 39 placebo) with 20 discontinuing at 2 years. The first primary outcome was achieved in 33 of 79 patients, 42% (95% CI 31–53), in the everolimus group, and none (0–39) of the placebo group with average exposure of 38 weeks. However, in 93% of the patients taking everolimus, their AMLs remained stable or shrank (with >30% shrinkage in 80%); whereas in 78% of patients on placebo, their AMLs did not shrink or continued to grow (Figure 1).
The median dose of drug administered was 8.6mg and mean everolimus trough levels ranged between 7.63ng/ml (week 2; SD 4.32) and 9.37ng/ml (SD 8.83) but with large inter-individual variability (56–94%).
There was a significant improvement in skin rash, with >70% clearance in 26% of patients on everolimus but in none of the patients on placebo, emphasising the biological effect.
While on treatment, seven female patients on everolimus developed amenorrhoea compared with one on placebo. Four of the women in the everolimus group recovered spontaneously while still taking the drug, and three did not, but opted to continue treatment. Other adverse events were common but mild and tolerable and similar to the known safety profile for everolimus when used in other conditions.
These included transient mouth ulcers, transient acne and some changes in blood test parameters that were not clinically significant. There were minor rises in plasma total cholesterol in some patients on everolimus. Three patients on everolimus discontinued due to allergic reactions. After all patients had been in the study for six months (the majority up to 12 months) the study investigators discontinued the placebo phase as an interim data analysis showed both study end points had reached significance. The median time to progression was 11 months in the patients on placebo. Eight (21%) of the placebo patients progressed.31 No patients on everolimus had progression of their AMLs. The majority of placebo patients swapped to everolimus treatment and the trial continues to assess long-term efficacy and potential side effects.
The longer-term follow up has shown that the efficacy of everolimus is not only durable but that there is also continued shrinkage of AMLs in those on treatment.Serious side effects remain rare, minor side effects are tolerable and the incidence of new side effects dramatically decreases over time.32
Pooled results from EXIST-1 and EXIST-2 so far have shown that renal function measured as estimated glomerular filtration rate is preserved in those patients who did not already have significant renal impairment prior to commencing the study.33
The results of EXIST-2 led to the recommendation (in the 2012 TSC consensus conference) that patients with TSC with angiomyolipomata of >3cm and enlarging should be treated with an mTOR inhibitor pre-emptively.22
The favourable efficacy and safety results from the mTOR inhibitor studies have led to a license being granted in the EU, USA and other countries. The licensed indication for everolimus (Votubia) is for the treatment of AMLs in adults who are at risk of complications and do not need emergency surgery or embolisation, and SEGA in all ages in those patients whose SEGA is not amenable to surgery. Everolimus is now funded directly or via access schemes in most developed countries including the EU, Scandinavia, USA, Australia, Russia, Slovakia, Slovenia, Romania, Japan, Taiwan, Thailand and Korea.
Delivery and outlook
Having a successful treatment is useless if patients cannot access the specialists they need. The National Health Service is in the process of setting up a national network of TSC clinics that will cohort expertise in TSC management, optimise cost-effective use of everolimus and promote ongoing research. mTOR inhibitors are unlike most other drugs in that they specifically target the underlying molecular pathology of this genetic disease. Given systemically they have potential benefits beyond the indication for which they are prescribed. As well as the efficacy for SEGA, renal AML, preliminary research has shown potential benefit of everolimus in refractory epilepsy.34 This is not a licensed indication but is currently being explored further in EXIST-3, a randomised, placebo-controlled trial looking at the efficacy and safety of everolimus as adjunctive therapy in patients with TSC-associated refractory partial-onset seizures. In addition, another mTOR inhibitor has been licensed for the treatment of pulmonary lymphangioleiomyomatosis by the US Food and Drug Administration on the basis of results from the MILES trial.35
Studies in animals and case reports have suggested mTOR inhibitors may be beneficial in preventing intellectual impairment and autism. These are also the subject of ongoing research trials: TRON; RAPIT; and a multicentre study in the USA by the TSC clinical trials collaboration (https://clinicaltrials.gov).
In animal models, early treatment with mTOR inhibitors can completely prevent the manifestations of TSC.36–38 The next direction in TSC research needs to be investigation of whether we can move on from rescue therapy to prevention by early treatment with mTOR inhibitors. This is now being explored (www.tuberous-sclerosis.org).
Because of the phenotypic variability in TSC, there is no substitute for thorough examination and investigation of patients who might have the condition. Until recently, treatments have been supportive in managing symptoms or potentially destructive rescue therapy. mTOR inhibition is likely to transform management of TSC and the results of the everolimus trials are being studied in further detail to see if the encouraging reductions in tumour size translate into improved outcomes for patients in the long term. Future research will show whether mTOR inhibition really is the ‘silver bullet’ for TSC.
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- Rayer PF. Traité des maladies de la peau / atlas (in French). Paris: J.B. Baillière 1835:20.
- Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015;14(7):733–45.
- Bombardieri R et al. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur J Paediatric Neurol 2010;14:146–9.
- Jozwiak S et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatric Neurol 2011;15:424–31.
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- European Medicines Agency. Public summary of opinion on orphan designation. Everolimus for the treatment of tuberous sclerosis 2010;1–4.
- Kingswood JC et al. TOSCA – First international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. Orphanet J Rare Dis 2014;9:182. www.ojrd.com/content/9/1/182 (accessed 24 August 2015).
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- Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int 2004;66:924–34.
- Kingswood JC et al. Real-world assessment of renal involvement in tuberous sclerosis complex (TSC) patients in the United Kingdom (UK). 29th Annual Congress of the European Association of Urology, Stockholm, Sweden. Eur Urol Suppl 2014;13:e318-e318a.
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- Consugar MB et al. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int 2008;74(11):1468–79.
- Cox J et al. The natural history of renal angiomyolipomata (AMLS) in tuberous sclerosis complex (TSC). Nephrology Dialysis Transplantation 2012;27:ii325. 49th ERA-EDTA Congress, Paris, France.
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- Eijkemans MJ et al. Long-term follow-up assessing renal angiomyolipoma treatment patterns, morbidity, and mortality: An observational study in tuberous sclerosis complex patients in the Netherlands. Am J Kidney Dis 2015; Jul 10 [Epub ahead of print].
- Northrup H et al; International Tuberous Sclerosis Complex Consensus. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol 2013;49(4):243–54.
- Krueger DA et al; International Tuberous Sclerosis Complex Consensus. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:255–65.
- National Institute for Health and Care Excellence. CKD guidelines 2014. www.nice.org.uk/guidance/cg182/chapter/1-recommendations (accessed 24 August 2015).
- Cabrera López C et al. Effects of rapamycin on angiomyolipomas in patients with tuberous sclerosis. Nefrologia 2011;31(3):292–8.
- Bissler JJ et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140–51.
- Davies DM et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: A phase 2 trial. Clin Cancer Res 2011;17:4071–81.
- Dabora SL et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: Kidney angiomyolipomas and other tumors regress and VEGF-D levels decrease. PLoS One 2011;6:e23379.
- Franz DN et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013;381(9861):125–32.
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For patients and families
- The UK Tuberous Sclerosis Association – www.tuberous-sclerosis.org
- NHS Choices website – www.nhs.uk/conditions/tuberous-sclerosis/Pages/Introduction.aspx
- BMJ Learning Module on TSC – http://learning.bmj.com/learning/module-intro/tuberous-sclerosis-.htmlmoduleId=10047149&searchTerm=“tuberous%20sclerosis”&page=1&locale=en_GB
- The International Guidelines – www.pedneur.com/article/S0887-8994%2813%2900490-6/fulltext– www.sciencedirect.com/science/article/pii/S0887899413004918
- The TAND (tuberous sclerosis-associated neuropsychiatric disorders) guidelines – www.tsalliance.org/tand