Renal angiomyolipoma (AML) is a common benign tumor of the kidney. AML can occur sporadically or may be associated with tuberous sclerosis complex (TSC).

1. In the name of God
MASTANEH MOGHTADARI
PEDIATRIC NEPHROLOGIST
CHILDREN´S HOSPITAL MEDICAL CENTER TEHRAN UNIVERSITY OF MEDICAL
SCIENCE

2. M-TOR in Management of Renal
Angiolipomyoma

3. Renal angiomyolipoma (AML) is a common benign tumor
of the kidney.
AML can occur sporadically or may be associated with
tuberous sclerosis complex (TSC).

4. AML is composed of blood vessels, smooth muscle, and fat
components.
Since AML presents various imaging findings depending on the
ratios of the three components, there might be difficulty in making
a confident diagnosis.
AMLs are classified into three types; classic AML, fat poor AML and
epithelioid AML.
Epithelioid AML exhibits aggressive clinical behavior, leading to
venous thrombus, distant metastasis, and death

5. •TSC is an autosomal dominant genetic disorder in which
hamartomas develop throughout the body and is associated with
various organ disorders.
•TSC is also associated with the formation of hamartomas on the
skin, retina, and nails.
•The main symptoms are subependymal nodules and subependymal
giant cell astrocytoma (SEGA) in the brain, AML in the kidney,
lymphangioleiomyomatosis in the lung, and rhabdomyoma in the
heart.

6. TSC associated AML occurs more frequently at a younger age than sporadic
AML and bilaterally at multiple sites.
The symptoms of AML are abdominal pain, a palpable mass, macroscopic
hematuria, and hypertension, but most patients are asymptomatic until their
tumors grow large.
RAML is associated with spontaneous bleeding and potentially life-threatening
hemorrhage if the lesion is > 4 cm in diameter
Renal AML rupture can result in shock and the patients suffer from severe
pain, with anemia advancing rapidly, and decreasing blood pressure.

7. Management
Observation and follow-up
AML is divided into the sporadic type and TSC-associated type.
Sporadic AML is usually asymptomatic and grows slowly.
Active surveillance is generally conducted for patients with small
(<4 cm) sporadic AMLs.
It is recommended fallow up with ultrasound, if needed CT and
MRI

8. In the past, renal trans arterial embolization (TAE), surgery (nephrectomy and
partial nephrectomy), and ablation procedures (percutaneous or laparoscopic
radiofrequency ablation, microwave ablation, and cryoablation) have been
recommended to manage symptoms due to a mass effect or bleeding, while
more recently everolimus has become the first-line medical treatment for
RAML in patients with TSC .
Everolimus is effective for noninvasively reducing the size of many RAMLs, but
its activity and limitations in patients with huge RAMLs of > 20 cm in the
longest diameter are unknown.

9. In cases with symptoms of AML, intervention is needed irrespective of the presence of TSC.
In cases with asymptomatic TSC-associated AML >3 cm in size, mTOR inhibitors are
recommended as the first-line treatment.
an intra-tumoral aneurysm of >5 mm, treatment, including TAE and partial nephrectomy (PN),
is required.

10. mTOR inhibitors
Everolimus is approved for the treatment of TSC-associated AML, SEGA, and advanced RCC
after failed tyrosine kinase inhibitor treatment.
The effect of everolimus on TSC-associated AML was investigated in the extension studies, in
which 6-month everolimus treatment reduced the AML volume by 50% in 55% of patients
Based on these results, the ITSCCC recommended mTOR inhibitors as a first-line treatment for
AML of 3 cm in size, even when asymptomatic. TAE and PN were recommended as second-line
treatments

11. •Ni et al retrospectively investigated the effect of short-term everolimus
treatment on TSC-associated AML in the Chinese population.
•In their study, the mean reduction rate in the tumor volume was 56.5% at 12
weeks after the treatment.
• Wang et al reported the volume responses to everolimus and sirolimus
treatments for TSC-associated AML
•The mean volume reductions of the AML in the everolimus and sirolimus
groups were 55.6% and 30.5%, respectively.
•They concluded that everolimus might be more effective than sirolimus for
the treatment of patients with TSC-associated AML.

12. •Kingswood et al. treated 30 patients with everolimus, whose maximum renal
size and median total renal volume were 198 and 10.9 cm3, respectively. After
12, 24, and 48 weeks of treatment, 56.5, 78.3, and 80.0% of the patients,
respectively, showed ≥50% reduction in the total volume of target RAMLs.
•Hatano et al. reported the effect of everolimus therapy in 40 RAML patients
with a maximum renal diameter of 4–10 cm (n = 32) or > 10 cm (n = 8). After 6
months, the mean percent reduction of lipid-rich lesions was 24%, whereas it
was 68% for solid lesions (p < 0.001). They concluded that everolimus could
reduce the size of RAML mainly consisting of angiomatous and leiomyomatous
tissue, but had a relatively poor effect on lipomatous RAML .
•There has been no report in the English literature about the effect of
everolimus on huge RAML > 20 cm in the longest diameter

13. TSC is an autosomal dominant disorder in which benign tumors develop in multiple organs,
including the skin, brain, and kidneys.
In TSC patients, mutation of the TSC1 or TSC2 gene leads to unregulated activation of mTOR
pathway.
mTOR inhibitors like everolimus reduce phosphorylation of downstream effectors of mTOR,
resulting in a decrease in DNA synthesis and cell proliferation that reduces the size of RAML
associated with TSC .
Because mTOR inhibitor therapy is noninvasive as well as being effective, it is recommended
as the first-line treatment for RAML, while selective embolization, kidney-sparing resection, or
ablation therapy are acceptable as second-line modalities

14. Cai et al reported that the most common adverse events associated with everolimus
treatment for TSC-associated AML were oral mucositis (100%), irregular menstruation (91%),
and abdominal pain (77.8%).
In another study, the main adverse events of everolimus were stomatitis (91%), irregular
menstruation (65%), i and proteinuria (17%). Grade 3 adverse events developed in of the
patients.
Blood testing, urinalysis, and radiography should be carried out once a month during
treatment for the management of these adverse events.

15. Adverse events of AFINITOR
Metabolic Disorders: Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have
been reported in patients taking AFINITOR at an incidence up to 75%, 86%, and 73%,
respectively. In nondiabetic patients, monitor fasting serum glucose prior to starting AFINITOR
and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently
as clinically indicated. Monitor lipid profile prior to starting AFINITOR and once yearly
thereafter. When possible, achieve optimal glucose and lipid control prior to starting
AFINITOR.
Myelosuppression: Anemia, lymphopenia, neutropenia, and thrombocytopenia have been
reported in patients taking AFINITOR. Monitor complete blood count prior to starting
AFINITOR, every 6 months for the first year of treatment, and annually thereafter. Withhold or
permanently discontinue AFINITOR based on severity.

16. stomatitis: Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients
treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial
experience.
Stomatitis most often occurs within the first 8 weeks of treatment. When starting AFINITOR,
initiating dexamethasone alcohol-free oral solution as a swish-and-spit mouthwash reduces
the incidence and severity of stomatitis. If stomatitis does occur, mouthwashes and/or other
topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-
containing products should be avoided. Antifungal agents should not be used unless fungal
infection has been diagnosed

17. Infections: AFINITOR has immunosuppressive properties and may predispose patients to
bacterial, fungal, viral, or protozoal infections, including those with opportunistic pathogens.
Localized and systemic infections, including pneumonia, mycobacterial infections, other
bacterial infections; invasive fungal infections, such as aspergillosis, candidiasis, or PJP; and
viral infections, including reactivation of hepatitis B virus, have occurred. Some of these
infections have been severe (eg, sepsis, sepsis shock, or resulting in multisystem organ failure)
or fatal. The incidence of serious infections was reported at a higher frequency in patients <6
years of age. Complete treatment of preexisting invasive fungal infections prior to starting
treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue
AFINITOR based on severity of infection. Administer prophylaxis for PJP when concomitant use
of corticosteroids or other immunosuppressive agents are required.

18. noninfectious Pneumonitis: Noninfectious pneumonitis is a class effect of rapamycin
derivatives. Noninfectious pneumonitis was reported in up to 19% of patients treated with
AFINITOR in clinical trials, some cases reported with pulmonary hypertension (including
pulmonary arterial hypertension) as a secondary event. Fatal outcomes have been observed.
Consider a diagnosis of noninfectious pneumonitis in patients presenting with nonspecific
respiratory signs and symptoms. Consider opportunistic infections such as Pneumocystis
jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any
new or worsening respiratory symptoms. Continue AFINITOR without dose alteration in
patients who develop radiological changes suggestive of noninfectious pneumonitis and have
few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis.
withhold or permanently discontinue AFINITOR based on severity. Corticosteroids may be
indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant
use of corticosteroids or other immunosuppressive agents are required. The development of
pneumonitis has been reported even at a reduced dose.

19. Everolimus can cause deterioration of renal function. In kidney transplant recipients, everolimus
treatment has been associated with an increase in proteinuria .
The proteinuria associated with everolimus was of mixed glomerular and tubular origin, and
occasionally reached the nephrotic range .
In a rat model, glomerular repair was inhibited by everolimus, leading to an increase in proteinuria,
glomerulosclerosis, interstitial fibrosis, and glomerular inflammation, as well as a decline in
creatinine clearance
While the precise association of everolimus with renal adverse events has not been established,
cessation of this drug is recommended if proteinuria increases to > 1 g/day (or especially to > 3
g/day) or if eGFR declines to < 30 mL/min
However, appropriate management of the adverse events associated with mTOR inhibitors is
necessary

20. Growing angiomyolipomata also have the potential to slowly
compress or infiltrate healthy renal tissue, compromising function
and increasing the risk for renal failure .
As a result, they are a significant cause of morbidity and mortality
in patients with TSC, highlighting the need for early detection and
treatment
everolimus was approved for the treatment of TSC-associated
angiomyolipoma in adult patients. More recently, longer-term
interim analysis of the data demonstrated a further improvement
in response rate to 54% after approximately 2.5 years

21. Everolimus is currently not approved to treat TSC-associated
angiomyolipomata in pediatric patients owing to a lack of data in this
subpopulation
Many patients with TSC enrolled in EXIST-1 also had angiomyolipoma, making
possible an evaluation of the effect of everolimus on angiomyolipoma in
pediatric patients.

22. In brief, patients of any age with a diagnosis of TSC and serial SEGA growth
were randomly assigned 2:1 to receive everolimus or placebo in the primary
core phase of the study. Everolimus was orally administered and initiated at a
dose of 4.5 mg/m2 body surface area per day and subsequently titrated to
blood trough levels of 5–15 ng/ml subject to tolerability. The primary end
point of the study was SEGA response rate, defined as the proportion of
patients with a ≥50% reduction in the sum SEGA volumes relative to baseline,
with no worsening of nontarget SEGA lesions, no new SEGA lesions (≥1 cm in
the longest diameter), and no new or worsening hydrocephalus.

23. More than half (54.5%) of the patients in this subgroup were male, and most
were white (90.9%; . The median (range) age of these patients was 11.5 (5.4–
17.5) years, with 39.4% aged between 3 and <10 years .
Most (81.8%) patients had a lesion size of <3 cm at baseline. At the time of
study completion , median duration of everolimus exposure in these patients
was 44.8 months (range 1.9–57.9). The mean everolimus trough concentration
(Cmin) increased over the first 6 weeks from 4.40 ng/ml at week 2, to 5.09
ng/mL at week 4, and 5.76 ng/ml at week 6, and then remained at
approximately between 6 and 8 ng/ml for the remainder of the study. All but
one patient (32 out of 33) had taken antiepileptic medications during the
study.

24. Among the 33 patients with angiomyolipoma at baseline, a renal
angiomyolipoma response was reported in 25 patients (75.8%, 95%
CI 57.7–88.9%) and stable disease was reported as a best response
in 4 patients (12.1%).
The mean percentage reduction of renal angiomyolipoma volume
improved from 47% at week 12 to 70.7% at week 96, and then
stabilized for the duration of the study remaining above 67%
through week 240.

25. All patients experienced ≥1 AE during the study, with most (n = 30;
90.9%) experiencing an AE that was suspected to be related to
everolimus.
The most commonly reported AEs of any grade occurring in more
than 25% of patients included convulsion and mouth ulceration
(45.5% each), stomatitis (42.4%), and cough (27.3%;. Four patients
(12.1%) were reported to have hypertension.

26. the effectiveness of everolimus in reducing SEGA volume with sustained
responses over approximately 4 years of treatment . A preplanned secondary
analysis was to evaluate the long-term efficacy and safety of everolimus in the
subgroup of pediatric patients with renal angiomyolipoma. Results from this
analysis demonstrate the effectiveness of everolimus in reducing renal
angiomyolipoma volume in these patients, with approximately 76% of patients
achieving an angiomyolipoma response. Most patients (>80%) achieved
angiomyolipoma volume reductions of at least 30% over the duration of the
study, and reductions of least 50% from week 24 onward, thus highlighting the
sustained efficacy of everolimus for treating TSC-related renal
angiomyolipoma in this pediatric subgroup.

27. Controlling the growth of angiomyolipomata is an important goal of treatment
to avoid the development of future complications.
The growth of angiomyolipomata may lead to the loss of normal renal tissue
and result in the development of chronic kidney disease (CKD) and subsequent
renal failure .
The vasculature of renal angiomyolipomata is often abnormal, resulting in the
development of aneurysms and increasing the risk of spontaneous
hemorrhage

28. Risk factors for angiomyolipoma-related hemorrhage include
angiomyolipoma size (i.e., >3 cm), aneurysm size >0.5 cm, and
serial tumor growth .
Angiomyolipoma-related renal hemorrhage is less common in the
pediatric setting, but cases have been previously reported, even in
children with small tumors . Close monitoring of renal
angiomyolipomata throughout life is warranted, along with early
treatment to control the growth of these tumors and potentially
reduce the risk for spontaneous renal hemorrhages

29. The majority of patients in the current analysis from EXIST-1 had
mostly negative or trace protein results on urinalysis, with
proteinuria being reported as an AE in only 2 patients, and
persistently elevated urinary protein levels occurring in 1 patient. It
should also be noted that some patients in the study were taking
antiepileptic medications, including topiramate. Topiramate has
been shown to induce metabolic acidosis accompanied by an
alkaline urine . Alkaline urine (pH >7.5) can lead to false-positive
results for proteinuria on urine dipstick tests . However, to ensure
safety, proteinuria should be monitored in everolimus-treated
patients.

30. In this analysis, everolimus effectively reduced angiomyolipoma
size, with reductions being sustained over a period of
approximately 4 years. Therefore, treatment with everolimus to
prevent the development of large lesions (i.e., >3 cm) in patients
with serial growth or aneurysm size >0.5 cm may be a means of
reducing the risk of bleeding and/or CKD among high-risk pediatric
patients.

31. CONCLUSION
The major aims of treatment for TSC-associated AML are to maintain renal
function and to prevent rupture and enlargement of the AML.
It is unclear how long physicians should continue everolimus treatment for
TSC-associated AML from the first administration. Everolimus can shrink AMLs
but not cure them.
Moreover, the long-term administration of everolimus increases the risk of
developing gonadal dysfunction, interstitial lung disease, and
immunosuppression-related complications.
patients should be monitored carefully during treatment with everolimus
because it may induce nephropathy with deterioration of renal function and
development of proteinuria

32. In conclusion, invasive renal EAML is a type of tumor with
malignant potential, and the complete tumor resection is a key
factor for cure. Gene mutation analysis of TSC1 and TSC2 should be
performed in the patient whose lesion can’t be resected
completely in preoperative assessment, or progressed after
surgery.
The mTOR inhibitor can be an effective treatment for patients with
invasive malignant renal EAML. Patients with TSC may benefit more
from the therapy.