Clinical Practice: Mini-Review
`
` Nephron 2016;134:51–58
` DOI: 10.1159/000448293
`
` Received: March 30, 2016
` Accepted after revision: July 6, 2016
` Published online: August 10, 2016
`
` Review of the Tuberous Sclerosis Renal
`Guidelines from the 2012 Consensus Conference:
`Current Data and Future Study
`
` J. Chris Kingswood   a John J. Bissler   d Klemens Budde   g John Hulbert   e
`Lisa Guay-Woodford   f Julian R. Sampson   c Matthias Sauter   h Jane Cox   a
`Uday Patel   b Frances Elmslie   b Chris Anderson   b Bernard A. Zonnenberg   i
`
` a   Sussex Kidney Unit, Royal Sussex County Hospital, Brighton , b   South West Thames Regional Genetics Service, St.
`Georges Hospital, London , and c   Institute of Medical Genetics, Cardiff University, Cardiff , UK; d   Lebonheur Children’s
`Hospital, University of Tennessee, and St. Jude Children’s Research Hospital, Memphis, Tenn. , e Urologic Physicians,
`PA, Edina, Minn. , and f   Children’s National Health System, Washington D.C. , USA; g   Department of Nephrology ,
`Charité Universitätsmedizin, Berlin , and h   Klinikverbund Kempten-Oberallgäu, Kempten , Germany; i   Oncology
`Department , Universitair Medisch Centrum, Utrecht , Netherlands
`
`
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` Key Words
` Tuberous sclerosis complex · Angiomyolipoma ·
`Embolization · Mammalian target of rapamycin inhibitors ·
`Everolimus · Sirolimus · Renal complications · Prevention ·
`Treatment guidelines
`
` Abstract
` Renal-related disease is the most common cause of tuberous
`sclerosis complex (TSC)-related death in adults, and renal an-
`giomyolipomas can lead to complications that include
`chronic kidney disease (CKD) and hemorrhage. International
`TSC guidelines recommend mammalian target of rapamycin
`(mTOR) inhibitors as first-line therapy for management of as-
`ymptomatic, growing angiomyolipomas >3 cm in diameter.
`This review discusses data regarding patient outcomes that
`were used to develop current guidelines for embolization of
`renal angiomyolipomas and presents recent data on 2 avail-
`able mTOR inhibitors – sirolimus and everolimus – in the
`treatment of angiomyolipoma. TSC-associated renal angio-
`myolipomas can recur after embolization. Both sirolimus
`and everolimus have shown effectiveness in reduction of an-
`giomyolipoma volume, with an acceptable safety profile
`
`that includes preservation of renal function with long-term
`therapy. The authors propose a hypothesis for mTORC1 hap-
`loinsufficiency as an additional mechanism for CKD and pro-
`pose that preventive therapy with mTOR inhibitors might
`have a role in reducing the number of angiomyolipoma-re-
`lated deaths. Because mTOR inhibitors target the underlying
`pathophysiology of TSC, patients might benefit from treat-
`ment of multiple manifestations with one systemic therapy.
`Based on recent evidence, new guidelines should be consid-
`ered that support the earlier initiation of mTOR inhibitor
`therapy for the management of renal angiomyolipomas to
`prevent future serious complications, rather than try to res-
`cue patients after the complications have occurred.
` © 2016 S. Karger AG, Basel
`
` Overview of Renal Disease in Tuberous Sclerosis
`Complex
`
` Guidelines relevant for tuberous sclerosis complex
`(TSC)-related angiomyolipoma, including updated diag-
`nostic criteria and surveillance and management recom-
`mendations, were developed from the second Interna-
`
` © 2016 S. Karger AG, Basel
`
`
`E-Mail karger@karger.com
` www.karger.com/nef
`
` Dr. J. Chris Kingswood
` Sussex Kidney Unit
` Royal Sussex County Hospital
` Eastern Road, Brighton BN2 5BE (UK)
` E-Mail chris.kingswood   @   bsuh.nhs.uk
`
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`Table 1. Kidney-related surveillance and management recommendations of the International Tuberous Sclerosis Complex Consen-
`sus Group [2]
`
` Ne wly diagnosed or suspected TSC
`
`Diagnosed with definite or possible TSC
`
`Surveillance of kidneys
`Obtain MRI of the abdomen to assess for the presence of
`angiomyolipoma and renal cysts
`Screen for hypertension by obtaining accurate blood pressure
`Evaluate renal function by determining GFR
`
`Obtain MRI of the abdomen to assess angiomyolipoma
`progression and renal cystic disease
`(every 1−3 years for life)
`Assess renal function (GFR and blood pressure) at least annually
`
`Clinical presentation
`
`Recommendation
`
`Management recommendations for renal angiomyolipoma
`Angiomyolipoma with acute hemorrhage
`
`Asymptomatic, growing angiomyolipoma >3 cm in diameter
`
`Embolization (followed by corticosteroids for 7 days to mitigate
`post-embolization syndrome) [3]. Embolization should be as
`selective as technically feasible to preserve renal parenchyma
`Avoid nephrectomy
`First-line: mTOR inhibitor
`Second-line: selective embolization or kidney-sparing resection
`
`tional TSC Consensus Conference in Washington, D.C.,
`USA [1, 2] , in which 79 experts from 14 countries par-
`ticipated. Table 1 summarizes the surveillance and man-
`agement recommendations relevant to the kidney. The
`nephrology subcommittee recommended the use of
`mammalian target of rapamycin (mTOR) inhibitors for
`first-line therapy for management of asymptomatic,
`growing angiomyolipomas >3 cm in diameter [1, 2] .
`These guidelines were based on a search of PubMed and
`Scopus databases performed on March 12, 2012, for the
`consensus guidelines [2] and of the OVID database from
`2000 to 2014. This review is based on those and subse-
`quent relevant published papers.
` The renal presentation of TSC most often encompasses
`renal cysts, angiomyolipoma, impaired kidney function
`and, more rarely, renal cell carcinoma (RCC) [4, 5] . Cysts
`occur in approximately 30–45% of patients with TSC and
`may be associated with kidney failure and hypertension
` [5] . The TSC2 and PKD1 contiguous gene-deletion syn-
`drome affects approximately 1 in 20 patients with TSC.
`People with this syndrome have deletions involving both
`the TSC2 and the PKD1 genes [6] ; in these patients, cystic
`disease is severe and commonly associated with early renal
`failure. Angiomyolipomas are benign tumors composed
`of blood vessels, smooth muscle-like cells, and adipose-
`like tissue [1] . They are rarely reported extrarenally but
`occur in the kidneys in up to 80% of patients with TSC and
`contribute to renal disease as the most common cause of
`TSC-related death [7]. A strong association between age,
`angiomyolipoma size, and chronic kidney disease (CKD)
`
`has been reported; patients with higher CKD stage tend to
`be older and have more advanced angiomyolipoma [8] .
`CKD may develop as a result of loss of renal parenchyma
`because of growth of angiomyolipoma or cysts, or as a
`complication from surgery or embolization [4, 8] . Fat-
`poor angiomyolipomas (i.e. the epithelioid variant) are
`commonly observed in patients with TSC, whereas in the
`general population, they account for <0.1% of angiomyo-
`lipomas [1, 5] . RCCs (occurring in 2–3% of patients with
`TSC) [5] may be confused diagnostically with fat-poor an-
`giomyolipomas [9, 10] . Contrast-enhanced MRI or CT
`may help in making this differentiation, but it remains
`challenging even in high volume centers. Biopsy might
`nevertheless be needed. A slower growth rate has been
`postulated as another way to distinguish fat-poor angio-
`myolipoma from RCC [10] .
` A retrospective analysis assessed the risk of long-term
`renal outcomes, including CKD, by evaluating records
`from patients diagnosed with TSC who were included in
`the UK Clinical Practice Research Datalink linked to the
`Hospital Episode Statistics database [11]. Overall, 105 of
`341 total TSC patients (31%) had renal involvement (de-
`fined as presence of renal cysts, polycystic kidney disease,
`CKD, kidney stones, or kidney neoplasms such as angio-
`myolipomas). Among adult patients, 38% (91 of 237 pa-
`tients) had recognized renal involvement or renal-related
`comorbidity (CKD, 35%; single cyst, 16%; hematuria,
`21%; anemia, 21%). The prevalence of CKD (stages 3–5)
`in the TSC population up to age 64 was greater in every
`age group compared with the UK general population. The
`
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`DOI: 10.1159/000448293
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`crude prevalence estimates showed that TSC patients de-
`veloped stage 3+ CKD 30 years earlier than the general
`UK population, and rates of stage 3+ CKD were more
`than 5 times higher than in the general UK population
`(relative risk 5.4, 95% CI 3.7–8.0; p < 0.001) [11].
` Patients with TSC-associated angiomyolipoma have
`an increased risk for hemorrhage, with risk factors con-
`sidered to be angiomyolipoma size (>3 or >4 cm), aneu-
`rysm size >0.5 cm, and serial growth [3, 7] . Although
`small angiomyolipomas are usually asymptomatic, angi-
`omyolipomas ≥ 4 cm become symptomatic in 68–80% of
`patients, with 50–60% presenting as hemorrhage [12] .
` Renal complications associated with TSC were also as-
`sessed in retrospective analyses of natural history data
`collected from 2 large databases [7]. The first analysis
`evaluated retrospective data collected by questionnaires
`from 296 patients with TSC in the UK Renal Registry.
`Twenty-seven of 52 patients (52%) with serial measure-
`ments of angiomyolipoma lesions captured over 5 years
`showed growth. Serial growth was found to be a risk fac-
`tor for bleeding (21% of patients with growing angiomyo-
`lipomas experienced renal bleeding, compared with only
`4% of patients with stable angiomyolipomas; χ 2  = 7.42;
`p < 0.01). The second analysis evaluated data from 278
`patients with TSC who were followed up at the St. George’s
`Hospital Clinic (London, UK), of whom 130 had renal
`angiomyolipoma. Data were analyzed from 53 adults
`with TSC and renal angiomyolipoma for whom serial im-
`aging data were available. Sixty-seven percent of the an-
`giomyolipomas exhibited serial growth in these adults,
`with a mean rate of growth of 5.5 mm/year. The growth
`rate of the angiomyolipomas was not correlated with the
`size of lesion or age of patient, although growth rate tend-
`ed to be greater in younger patients [7].
`
` Outcome of Intervention
`
` From our review, we identified 16 case series that re-
`ported embolization of renal angiomyolipoma with suf-
`ficient data to characterize patient details and outcomes
`(online suppl. table 1; for all online suppl. material, see
`www.karger.com/doi/10.1159/000448293). Thereby, we
`found that after embolization, approximately 25% of
`TSC-associated renal angiomyolipoma recur.
` The incidence of CKD was assessed in a retrospective
`chart review of a TSC cohort treated in a single center in
`the Netherlands [13] . The mean duration of follow-up was
`15.8 years, and the median age at the end of follow-up was
`40 years. Of 351 patients with TSC, 244 (69.5%) had con-
`
`firmed renal angiomyolipoma. Patients were assigned a re-
`nal angiomyolipoma stage (from none detected to 6) based
`on the number of angiomyolipomas in both kidneys, size
`of angiomyolipoma, and kidney anatomy ( table 2 ). Fifty-
`nine percent of patients (144 of 244) with a confirmed renal
`angiomyolipoma reached a highest angiomyolipoma stage
` ≥ 3, which indicated that the patient was at a high risk for
`hemorrhage and was a candidate for elective embolization.
`Hypertension, anemia, impaired kidney function, and
`need for blood transfusions increased with angiomyolipo-
`ma stage. Patients in higher stages were more likely to re-
`quire more embolization. Yearly embolization rates ranged
`from 0.08 to 0.14 depending on angiomyolipoma stage,
`suggesting that patients with large, growing asymptomatic
`angiomyolipomas will require an embolization every 7–11
`years. Additionally, impaired kidney function was more
`common in patients who had undergone embolization
`(29%) than in those who had not (10%) [13] .
`
` Effectiveness/Risk of mTOR Inhibitors
` mTOR inhibitors represent the first systemic approach
`to treating the underlying pathophysiology of TSC dis-
`ease by blocking the activation of mTOR complex 1 and
`downstream signaling ( fig. 1 ) [5] . Two oral mTOR in-
`hibitors – sirolimus and everolimus – have been evalu-
`ated for management of angiomyolipoma (online suppl.
`table 2). Four small, open-label studies showed the effec-
`tiveness of sirolimus in the management of renal angio-
`myolipoma [14–17] .
` Data pertaining to the effects of everolimus on angio-
`myolipoma are more robust; results from 2 large random-
`ized, double-blind, placebo-controlled, phase 3 trials are
`available [18, 19] . In a subgroup analysis of patients in the
`EXIST-1 trial, after a median follow-up duration of 9.7
`months, angiomyolipoma response rate (an exploratory
`end point) was 53.3% for everolimus compared with 0%
`for placebo. Angiomyolipoma volume reductions with
`everolimus were sustained over 48 weeks of treatment
`( fig. 2 ) [20] . In EXIST-2, the primary end point of angio-
`myolipoma response was achieved in 42% of patients (33
`of 79) compared with 0% for placebo (0 of 39, p < 0.0001)
`after a median everolimus exposure of 8.7 months, and
`the median time to reach an angiomyolipoma response
`was 2.9 months [18] . Data from an open-label extension
`of the EXIST-2 study showed sustained reduction in an-
`giomyolipoma volume to at least 192 weeks of treatment
`( fig. 3 ), with an angiomyolipoma response rate of 56.3%
`(63 of 112 patients) over a median 39.8 months of evero-
`limus exposure. Among the 63 patients achieving angio-
`myolipoma response at any time, only 2 progressions
`
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` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
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`Color version available online
`
`Rapamycin
`(sirolimus
`or
`everolimus)
`
`Amino
`acid
`
`Glucose
`
`IGF
`
`Extracellular
`
`IGF1R
`
`Cell membrane
`
`FMRP
`
`PI3K
`
`Ras
`
`TSC2
`TSC1
`
`Akt
`
`NF1
`
`FKBP 12
`
`Rheb
`
`mTORC1
`
`Intracellular
`
`NF2
`
`Ribosome
`biogenesis
`
`mRNA
`translation
`
`Autophagy
`
`Cell growth and proliferation
`
` Fig. 1. The mTOR pathway.
`
`Table 2. Renal angiomyolipoma staging criteria proposed in a retrospective study
`
`Stage
`
`Angiomyolipoma number
`
`Angiomyolipoma size Description of kidney anatomy
`
`None detecteda None ≥1 cm in longest diameter
`1
`≤5
`2
`>5
`3
`≤5
`4
`>5
`5
`>5
`6
`>5
`
`–
`<3.5 cm
`<3.5 cm
`At least 1 ≥3.5 cm
`1–4 ≥3.5 cm
`5 or more ≥3.5 cm
`At least 1 ≥5.0 cm
`
`Normal
`Normal
`Normal
`Kidney intact
`Kidney intact
`Kidney recognizable
`Kidney not recognizable
`
` a Angiomyolipoma not detectable or lesions <1 cm unidentifiable as angiomyolipoma. Reprinted with permis-
`sion from Eijkemans et al. [13].
`
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`

`Reduction from baseline
`(cid:150)50%
`(cid:150)30%
`>0%
`
`(n = 1)
`16.7
`(n = 1)
`16.7
`
`(n = 4)
`36.4
`
`(n = 2)
`18.2
`
`(n = 6)
`50.0
`
`(n = 1)
`
`8.3
`
`(n = 10)
`
`100
`
`(n = 10)
`
`100
`
`(n = 23)
`
`100
`
`(n = 23)
`
`100
`
`(n = 8)
`80.0
`
`(n = 18)
`
`78.3
`
`(n = 23)
`
`100
`
`(n = 19)
`
`82.6
`
`(n = 13)
`
`56.5
`
`Week 12
`(n = 23)
`
`Week 24
`(n = 23)
`
`Week 48
`(n = 10)
`
`Week 12
`(n = 12)
`
`Week 24
`(n = 11)
`
`Week 48
`(n = 6)
`
`0
`
`0
`
`0
`
`Everolimus
`
`Placebo
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Percentage of patients with
`
`tumor reductiona (n)
`
` Fig. 2. Percentage change from baseline of sum of volumes (3 cm3) of target angiomyolipoma lesions by time
`window. Percentages were calculated relative to the number of patients evaluated at baseline and at the corre-
`sponding visit. Reproduced with permission from Kingswood et al. [20] .
`
`were observed. Long-term data show continued shrink-
`age of angiomyolipoma with everolimus therapy. Nota-
`bly, at this cutoff, no bleeding was observed with everoli-
`mus in a population with high risk for bleeding events
`before the initiation of the mTOR inhibitor therapy [21].
`
` Safety of mTOR Inhibitors
`
` Class effects of mTOR inhibitors include stomatitis/
`mucositis/mouth ulceration ( ∼ 50%), hypercholesterol-
`emia (20–40%), hypertriglyceridemia (12–50%), infec-
`tions (40–70%), hypophosphatemia (11%), amenorrhea
`(13–38%), hematologic abnormalities (leukopenia, neu-
`tropenia, 10–40%), and proteinuria (4–30%) [14–19] .
`The EXIST-2 extension data show a decrease in the num-
`ber of newly emergent adverse effects over time [22] . In
`addition, data from the 3.5-year analysis of EXIST-2 re-
`ported that severe renal impairment (glomerular filtra-
`tion rate (GFR) <30 ml/min/1.73 m 2 ) was observed in
`only 7.1% of patients, all of whom had compromised re-
`nal function prior to everolimus initiation. Furthermore,
`overall GFR remained stable over time; median GFR at
`baseline was 85 ml/min/1.73 m 2 and median GFR at week
`120 was 84 ml/min/1.73 m 2 [21].
`
` Potential Mechanisms for Renal Complications
` CKD may not be entirely attributable to angiomyoli-
`poma hemorrhage and subsequent treatment (i.e. sur-
`gery/embolization). A mechanism independent of bleed-
`ing may occur where large, benign angiomyolipomas en-
`croach on normal renal tissue and lead to CKD [5] . We
`propose 2 additional hypotheses for the development of
`CKD. The first postulates that normal replacement renal
`tissue becomes TSC tissue because of somatic second-hit
`mutations [23] occurring during rapid cell division (when
`the kidney still has growth and repair potential at age
`<35–40); this would cause an accelerated loss of normal
`renal tissue leading to CKD. A second hypothesis is that
` TSC1 or TSC2 haploinsufficiency may lead to modest
`mTORC1 overactivity and, therefore, glomerular hyper-
`trophy and hyperfiltration. It has been postulated that
`mTORC1 overactivity is a mechanism of CKD progres-
`sion, especially in diabetic nephropathy [24] and may be
`one mechanism by which patients with TSC develop
`CKD in middle age. Data show that mTOR is activated in
`patients with diabetic nephropathy and that inhibition of
`mTOR signaling prevented glomerulosclerosis and ame-
`liorated progression of glomerular disease in a mouse
`model [25] . In addition, either haploinsufficiency or sec-
`ond somatic mutation in the tubule cells could predispose
`
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`
` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
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`(cid:150)30% reduction
`(cid:150)50% reduction
`
`84.3
`
`67.1
`
`81.8
`68.2
`
`79.0
`
`62.0
`
`80.6
`
`63.3
`
`96
`48
`Time (weeks)
`
`11
`100
`
`22
`98
`
`144
`
`33
`70
`
`192
`
`44
`22
`
`80.6
`
`55.3
`
`24
`
`6
`103
`
`py is discontinued [14, 16] , so that therapy may need to
`be lifelong.
` Preliminary evidence has shown that early treatment
`of renal angiomyolipomas in children prevents progres-
`sion and preserves renal function [20] . To date, follow-up
`data have shown that risk for serious adverse events in
`this population is low and suggest that growth and phys-
`ical development in treated children are normal, although
`long-term issues such as potential effects on fertility ne-
`cessitate further study [26] .
` Patients with TSC are at lifelong risk for appearance
`and progression of many of TSC-associated complica-
`tions. With the availability of oral mTOR inhibitors, the
`underlying pathogenic dysregulation of mTORC1 signal-
`ing can be controlled, which might allow multiple clinical
`manifestations to be treated with a single-targeted thera-
`py. The potential benefits of preventive therapy in reduc-
`ing angiomyolipoma-related morbidities may outweigh
`the risks of long-term therapy. Furthermore, because oth-
`er complications of TSC also respond to mTOR inhibitor
`therapy, including subependymal giant cell astrocytomas
` [19] , facial angiofibromas [18, 19] , lymphangioleiomyo-
`matosis [27, 28] , and epilepsy [29] , a holistic approach to
`preventive therapy might be appropriate to avoid many
`serious manifestations of the condition.
`
` Conclusions
`
` Based on recent evidence, the 2012 international
`guidelines for the management of angiomyolipomas
`should be updated to include the use of mTOR inhibitor
`
`75.0
`
`44.2
`
`12
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Patients (%)
`
` Fig. 3. Long-term efficacy of everolimus
`from EXIST-2: proportion of patients with
` ≥ 30% or ≥ 50% reduction in angiomyolipo-
`ma volume over time [21].
`
`Time (months)
`All patients (n)
`
`3
`104
`
`to premature apoptosis or maldifferentiation, or might be
`associated with loss of function due to an undiscov-
`ered  novel mechanism (e.g. microcystic renal disease)
`that may not be identified by imaging. If this hypothesis
`is correct, mTOR inhibition might help ameliorate the
`loss of GFR independent of its effect on renal angiomyo-
`lipomas. However, it has also been postulated that mTOR
`inhibition may potentially worsen the progression of
`CKD [24, 25] , and additional research in this area is nec-
`essary.
`
` Investigating a Possible New Treatment Paradigm
`
` We propose a clinical trial in which mTOR inhibitors
`are used earlier to prevent progression of renal disease
`in TSC, not just as rescue therapy. The use of mTOR in-
`hibitors is nephron sparing, compared with emboliza-
`tion or surgery, and usually prevents further growth of
`angiomyolipoma [4] . Patients with TSC have a high a
`priori risk for severe renal disease, with approximately
`40% progressing to CKD by age 45–54 [11]. Data from
`EXIST-1 and EXIST-2 support the success of early treat-
`ment in preventing the progression of renal disease. If
`haploin sufficiency of TSC1 or TSC2 does cause hyper-
`filtration, then the risks of mTOR inhibitors may be
`counterbalanced by the increased benefit of downregu-
`lating mTOR overactivity in affected cells. However,
`there is as yet no published evidence in humans to sup-
`port any benefit beyond controlling angiomyolipomas.
`Furthermore, the current published evidence suggests
`that angiomyolipomas regrow if mTOR inhibitor thera-
`
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`therapy as first choice for preemptive treatment of grow-
`ing angiomyolipomas >3 cm in diameter. In addition, we
`propose a new study to determine the efficacy and risks
`of initiating preventive treatment in younger patients
`with a high angiomyolipoma burden (e.g. >5) before the
`tumors grow larger than 3 cm.
`
` Acknowledgments
`
` The authors acknowledge the TS Alliance for sponsoring the
`Consensus Conference and preceding literature review, which
`contributed to the findings reported. Novartis was one of the
`sponsors of the conference, but they did not participate in the
`conference or play a role in defining the recommendations. The
`authors also acknowledge the UK TSA for sponsoring the
` research into kidney disease reported from Brighton and St.
`Georges.
` Medical writing assistance was provided by Traci Stuve, MA,
`and Denise Balog, PharmD, of ApotheCom, with funding from
`Novartis.
`
` Disclosure Statement
`
` K.B., J.C.K., J.R.S., B.A.Z., M.S. and J.J.B. have received hono-
`raria and/or research grants or served as consultants for Novartis.
`K.B. has also served as consultant for Bristol-Myers Squibb, Effi-
`mune, Hexal, Pfizer, and Veloxis, and has received research grants
`for clinical studies, speaker fees, honoraria, travel expenses, and
`payment for development of educational presentations from As-
`tellas, Aicuris, BmT GmbH, Bristol-Myers Squibb, Chiesi, Frese-
`nius, Hexal, Otsuka, Pfizer, Roche, Siemens, and Veloxis. J.H. and
`F.E. have received speaker fees from Novartis and are members of
`the National Scientific Advisory Board of the Tuberous Sclerosis
`Alliance, for which they receive no compensation. J.R.S. serves on
`the Tuberous Sclerosis Alliance International Scientific Advisory
`Board (non-remunerated). L.G.-W. has served as a consultant for
`Otsuka and is a member of the Board of Trustees for the Polycystic
`Kidney Disease Foundation, for which she receives no compensa-
`tion. U.P. has received travel expenses from Novartis to speak at a
`conference on Tuberous Sclerosis. J.C. has received honoraria
`(paid to a renal charity) for serving on an advisory board for No-
`vartis, and is a former employee of the Tuberous Sclerosis Asso-
`ciation. C.A. has received speaker fees from Novartis and also trav-
`el expenses to speak at conference on Tuberous Sclerosis.
`
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