throbber
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
`
`
`66.28.38.188 - 12/2/2016 6:31:28 PM
`Downloaded by:
`
` 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
`
`Ex. 1120-0001
`
`

`
`66.28.38.188 - 12/2/2016 6:31:28 PM
`Downloaded by:
`
`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
`
`52
`
` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
`
` Kingswood    et al.
`
`Ex. 1120-0002
`
`

`
`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
`
`66.28.38.188 - 12/2/2016 6:31:28 PM
`Downloaded by:
`
`53
`
` TSC Renal Guidelines
`
` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
`
`Ex. 1120-0003
`
`

`
`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].
`
`66.28.38.188 - 12/2/2016 6:31:28 PM
`Downloaded by:
`
`54
`
` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
`
` Kingswood    et al.
`
`Ex. 1120-0004
`
`

`
`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
`
`100
`
`(n = 10)
`
`(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
`
`66.28.38.188 - 12/2/2016 6:31:28 PM
`Downloaded by:
`
`55
`
` TSC Renal Guidelines
`
` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
`
`Ex. 1120-0005
`
`

`
`66.28.38.188 - 12/2/2016 6:31:28 PM
`Downloaded by:
`
`(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-
`
`56
`
` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
`
` Kingswood    et al.
`
`Ex. 1120-0006
`
`

`
`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.
`
` References
`
` 1 Northrup H, Krueger DA; International Tu-
`berous Sclerosis Complex Consensus Group:
`Tuberous sclerosis complex diagnostic criteria
`update: recommendations of the 2012 inter-
`national tuberous sclerosis complex consen-
`sus conference. Pediatr Neurol 2013; 49: 243–
`254.
` 2 Krueger DA, Northrup H; International Tu-
`berous Sclerosis Complex Consensus Group:
`Tuberous sclerosis complex surveillance and
`management: recommendations of the 2012
`international tuberous sclerosis complex con-
`sensus conference. Pediatr Neurol 2013; 49:
` 255–265.
` 3 Bissler JJ, Racadio J, Donnelly LF, Johnson
`ND: Reduction of postembolization syn-
`drome after ablation of renal angiomyolipo-
`ma. Am J Kidney Dis 2002; 39: 966–971.
` 4 Pirson Y: Tuberous sclerosis complex-associ-
`ated kidney angiomyolipoma: from contem-
`plation to action. Nephrol Dial Transplant
`2013; 28: 1680–1685.
` 5 Budde K, Gaedeke J: Tuberous sclerosis com-
`plex-associated angiomyolipomas: focus on
`mTOR inhibition. Am J Kidney Dis 2012; 59:
` 276–283.
` 6 Kozlowski P, Roberts P, Dabora S, Franz D,
`Bissler J, Northrup H, Au KS, Lazarus R,
`Domanska-Pakiela D, Kotulska K, Jozwiak
`S, Kwiatkowski DJ: Identification of 54
`large  deletions/duplications in TSC1 and
`TSC2 using MLPA, and genotype-pheno-
`type correlations. Hum Genet 2007; 121:
` 389–400.
`
` 7 Kingswood JC, Doyle T, Cox J, Mbundi J, At-
`tard V, Patel U, Saggar A, Elmslie F: The nat-
`ural history of renal angiomyolipomata in tu-
`berous sclerosis complex. Paris, Presented at
`the 49th ERA-EDTA Congress, May 24–27,
`2012.
` 8 Vekeman F, Magestro M, Karner P, Duh MS,
`Nichols T, van Waalwijk van Doorn-Khos-
`rovani SB, Zonnenberg BA: Kidney involve-
`ment in tuberous sclerosis complex: the im-
`pact on healthcare resource use and costs. J
`Med Econ 2015; 18: 1060–1070.
` 9 Baskin HJ Jr: The pathogenesis and imaging
`of the tuberous sclerosis complex. Pediatr Ra-
`diol 2008; 38: 936–952.
` 10 Patel U, Simpson E, Kingswood JC, Saggar-
`Malik AK: Tuberose sclerosis complex: analy-
`sis of growth rates aids differentiation of renal
`cell carcinoma from atypical or minimal-fat-
`containing angiomyolipoma. Clin Radiol
`2005; 60: 665–673.
`11 Kingswood JC, Demuth D, Nasuti P, Luc-
`chese L, Gray E, Magestro M: Real-world
` assessment of renal involvement in tuber-
`ous sclerosis complex (TSC) patients in the
`United Kingdom (UK). Stockholm, Present-
`ed at the European Association of Urology,
`April 11–15, 2014.
` 12 Halpenny D, Snow A, McNeill G, Torreggiani
`WC: The radiological diagnosis and treat-
`ment of renal angiomyolipoma-current sta-
`tus. Clin Radiol 2010; 65: 99–108.
` 13 Eijkemans MJ, van der Wal W, Reijnders LJ,
`Roes KC, van Waalwijk van Doorn-Khos-
`rovani SB, Pelletier C, Magestro M, Zonnen-
`
`berg B: Long-term follow-up assessing renal
`angiomyolipoma treatment patterns, mor-
`bidity, and mortality: an observational study
`in tuberous sclerosis complex patients in the
`Netherlands. Am J Kidney Dis 2015; 66: 638–
`645.
` 14 Bissler JJ, McCormack FX, Young LR, El-
`wing JM, Chuck G, Leonard JM, Schmithorst
`VJ, Laor T, Brody AS, Bean J, Salisbury S,
`Franz DN: Sirolimus for angiomyolipoma in
`tuberous sclerosis complex or lymphangi-
`oleiomyomatosis. N Engl J Med 2008; 358:
` 140–151.
` 15 Davies DM, de Vries PJ, Johnson SR, Mc-
`Cartney DL, Cox JA, Serra AL, Watson PC,
`Howe CJ, Doyle T, Pointon K, Cross JJ, Tat-
`tersfield AE, Kingswood JC, Sampson JR: Si-
`rolimus therapy for angiomyolipoma in tu-
`berous sclerosis and sporadic lymphangi-
`oleiomyomatosis: a phase 2 trial. Clin Cancer
`Res 2011; 17: 4071–4081.
` 16 Dabora SL, Franz DN, Ashwal S, Sagalowsky
`A, DiMario FJ Jr, Miles D, Cutler D, Krueger
`D, Uppot RN, Rabenou R, Camposano S,
`Paolini J, Fennessy F, Lee N, Woodrum C,
`Manola J, Garber J, Thiele EA: Multicenter
`phase 2 trial of sirolimus for tuberous sclero-
`sis: kidney angiomyolipomas and other tu-
`mors regress and VEGF-D levels decrease.
`PLoS One 2011; 6:e23379.
` 17 Cabrera-Lopez C, Marti T, Catala V, Torres F,
`Mateu S, Ballarin J, Torra R: Assessing the ef-
`fectiveness of rapamycin on angiomyolipoma
`in tuberous sclerosis: a two years trial. Or-
`phanet J Rare Dis 2012; 7: 87.
`
`66.28.38.188 - 12/2/2016 6:31:28 PM
`Downloaded by:
`
`57
`
` TSC Renal Guidelines
`
` Nephron 2016;134:51–58
`DOI: 10.1159/000448293
`
`Ex. 1120-0007
`
`

`
` 18 Bissler JJ, Kingswood JC, Radzikowska E,
`Zonnenberg BA, Frost M, Belousova E, Sauter
`M, Nonomura N, Brakemeier S, de Vries PJ,
`Whittemore VH, Chen D, Sahmoud T, Shah
`G, Lincy J, Lebwohl D, Budde K: Everolimus
`for angiomyolipoma associated with tuberous
`sclerosis complex or sporadic lymphangi-
`oleiomyomatosis (EXIST-2): a multicentre,
`randomised, double-blind, placebo-con-
`trolled trial. Lancet 2013; 381: 817–824.
` 19 Franz DN, Belousova E, Sparagana S, Bebin
`EM, Frost M, Kuperman R, Witt O, Kohrman
`MH, Flamini JR, Wu JY, Curatolo P, de Vries
`PJ, Whittemore VH, Thiele EA, Ford JP, Shah
`G, Cauwel H, Lebwohl D, Sahmoud T, Joz-
`wiak S: Efficacy and safety of everolimus for
`subependymal giant cell astrocytomas associ-
`ated with
`tuberous
`sclerosis complex
`( EXIST-1): a multicentre, randomised, place-
`bo-controlled phase 3 trial. Lancet 2013; 381:
` 125–132.
` 20 Kingswood JC, Jozwiak S, Belousova ED,
`Frost MD, Kuperman RA, Bebin EM, Korf
`BR, Flamini JR, Kohrman MH, Sparagana SP,
`Wu JY, Brechenmacher T, Stein K, Berkowitz
`N, Bissler JJ, Franz DN: The effect of everoli-
`mus on renal angiomyolipoma in patients
`with tuberous sclerosis complex being treated
`for subependymal giant cell astrocytoma:
`subgroup results from the randomized, place-
`bo-controlled, Phase 3 trial EXIST-1. Nephrol
`Dial Transplant 2014; 29: 1203–1210.
`
`21 Bissler JJ, Kingswood C, Radzikowska E,
`Zonnenberg BA, Frost M, Belousova E, Sau-
`ter M, Nonomura N, Brakemeier S, de Vries
`PJ, Berkowitz N, Peyrard S, Budde K: Evero-
`limus for renal angiomyolipoma associated
`with tuberous sclerosis complex (TSC) from
` EXIST-2: continued efficacy and diminish-
`ing adverse events after ~3.5 years of treat-
`ment. Madrid, Presented at the 30th Annual
` European Association of Urology Congress,
`March 20–24, 2015.
` 22 Bissler JJ, Kingswood JC, Radzikowska E,
`Zonnenberg BA, Frost M, Belousova E, Sauter
`M, Nonomura N, Brakemeier S, de Vries PJ,
`Berkowitz N, Miao S, Segal S, Peyrard S,
`Budde K: Everolimus for renal angiomyoli-
`poma in patients with tuberous sclerosis com-
`plex or sporadic lymphangioleiomyomatosis:
`extension of a randomized controlled trial.
`Nephrol Dial Transplant 2015; 31: 111–119.
` 23 Astrinidis A, Henske EP: Tuberous sclerosis
`complex: linking growth and energy signaling
`pathways with human disease. Oncogene
`2005; 24: 7475–7481.
` 24 Decleves AE, Sharma K: Novel targets of an-
`tifibrotic and anti-inflammatory treatment in
`CKD. Nat Rev Nephrol 2014; 10: 257–267.
` 25 Godel M, Hartleben B, Herbach N, Liu S,
`Zschiedrich S, Lu S, Debreczeni-Mor A, Lin-
`denmeyer MT, Rastaldi MP, Hartleben G,
`Wiech T, Fornoni A, Nelson RG, Kretzler M,
`Wanke R, Pavenstadt H, Kerjaschki D, Cohen
`CD, Hall MN, Ruegg MA, Inoki K, Walz G,
`Huber TB: Role of mTOR in podocyte func-
`tion and diabetic nephropathy in humans and
`mice. J Clin Invest 2011; 121: 2197–2209.
`
` 26 Franz DN, Belousova E, Sparagana S, Bebin
`EM, Frost M, Kuperman R, Witt O, Kohrman
`MH, Flamini JR, Wu JY, Curatolo P, de Vries
`PJ, Berkowitz N, Anak O, Niolat J, Jozwiak S:
`Everolimus for subependymal giant cell as-
`trocytoma in patients with tuberous sclerosis
`complex: 2-year open-label extension of the
`randomised EXIST-1 study. Lancet Oncol
`2014; 15: 1513–1520.
` 27 McCormack FX, Inoue Y, Moss J, Singer LG,
`Strange C, Nakata K, Barker AF, Chapman JT,
`Brantly ML, Stocks JM, Brown KK, Lynch JP
`3rd, Goldberg HJ, Young LR, Kinder BW,
`Downey GP, Sullivan EJ, Colby TV, McKay
`RT, Cohen MM, Korbee L, Taveira-DaSilva
`AM, Lee HS, Krischer JP, Trapnell BC; Na-
`tional Institutes of Health Rare Lung Diseases
`Consortium; MILES Trial Group: Efficacy
`and safety of sirolimus in lymphangioleiomy-
`omatosis. N Engl J Med 2011; 364: 1595–1606.
` 28 Goldberg HJ, Harari S, Cottin V, Rosas IO,
`Peters E, Biswal S, Cheng Y, Khindri S,
`Kovarik JM, Ma S, McCormack FX, Henske
`EP: Everolimus for the treatment of lymphan-
`gioleiomyomatosis: a phase II study. Eur
`Respir J

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket