- mTOR is a protein kinase that interacts with other proteins to form two complexes, mTORC1 and mTORC2, which have different functions and sensitivities to the immunosuppressant rapamycin. mTOR inhibitors like sirolimus and everolimus bind to FKBP12 to inhibit mTORC1 and the proliferation of T cells. - mTOR inhibitors have beneficial effects in kidney transplantation by immunosuppression, reducing cancer risk and viral infections, and protecting heart health. They are used in combination with other drugs or to replace calcineurin inhibitors, but careful dosing is needed due to interactions with CYP3A4 inhibitors and inducers.

1. 6/17/2021 1

2. mTORi in Kidney Transplantation
Dr. Alaleh Gheissari,
Professor of Pediatrics
Pediatric nephrologist
6/17/2021 2

3. Main Topics
• Overview of mTOR Components and Signaling Pathways
• Common mTORi drugs
• mTORi based regimens in KTx
• Pros AND Cons
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4. Overview of mTOR Components and
Signaling Pathways
• mTOR is a 289 kDa protein kinase encoded in humans by the
MTOR gene .
• It interacts with several proteins to form mTORC1 and
mTORC2 among eukaryotes.
• There are two common proteins shared by mTORC1/mTORC2
multimeric complexes: the positive regulator mLST8 and the
negative regulator Deptor.
– Remember that there are unique proteins coupled to each complex
(stabilizers and inhibitors).
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5. Overview of mTOR Components and
Signaling Pathways
• The mTOR-containing complexes also differ in terms of
upstream modulators, substrate specificity, functional
outputs, and sensitivity to rapamycin.
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6. Overview of mTOR Components and
Signaling Pathways: mTORC1
mTORC1:
• broadly senses nutrients, growth factors, mitogens, and
stress signals.
• Responsible for cell growth by regulating important
cellular processes:
– including the translation of mRNAs into the synthesis
of key proteins for proliferation, lipid synthesis,
mitochondrial biogenesis, and autophagy
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7. Overview of mTOR Components and
Signaling Pathways: mTORC2
mTORC2:
• Upstream modulators and downstream effector proteins is
not as well understood.
• Insulin and related pathways : the main activators ??
• It has important consequences on cell survival,
cytoskeleton organization, and cycle progression.
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8. Overview of mTOR Components and
Signaling Pathways
• The sensitivity to rapamycin is another important feature that
distinguishes mTORC1 and mTORC2 complexes.
• Rapamycin does not directly inhibit the catalytic (kinase)
activity of mTOR
• It binds to the immunophilin FKBP12 (a protein that couples
with mTOR FKBP-rapamycin binding domain).
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9. How do mTOR inhibitors work?
• Bind FKBP12 and form the mTOR inhibitor–FKBP12 complex,
which directly binds and inhibits mTORC1.
• Inhibit the proliferation of antigen-activated T cells by
blocking their growth factor signaling pathways and arresting
the cells in the G1 stage of the cell cycle.
• Inhibit the proliferation of vascular muscle and cancer cells.
• Inhibit atherogenic remodeling and neointima formation.
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11. Effects of inhibitors on the alloimmune
response.
• Belatacept
• Calcineurin inhibitors
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12. Effects of inhibitors on the alloimmune
response.
• Anti-CD25 mAb
• mTOR inhibitors
• Mycophenolate,
azathioprine
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14. Treatment
regimen
Patients who might benefit Disadvantages
De novo
mTOR-I-
based
without CNI
Low immunological risk patients Wound-healing
problems in obese
patients
- CNI-related side effects to be anticipated
(neurotoxicity,
nephrotoxicity, CNI-associated hemolytic uremic
syndrome)
High incidence of
side effects of
mTOR-I and
mycophenolate
combination
Patients at risk of CMV or BKV infection Probably induction
with lymphocyte-
depleting
antibodies
necessary
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15. Treatment
regimen
Patients who might benefit Disadvantages
De novo
mTOR-I and
CNI
combination
Low and intermediate immunological risk
patients
Wound-healing
problems in obese
patients
Patients who do not tolerate an adequate dose of
mycophenolate
Possible risk of new-
onset diabetes
Patients at risk of CMV or BKV infection
Patients at risk of post-transplant malignancy
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16. mTORi Drugs
• Sirolimus (Rapamune)
• Everolimus( Certican/Certikan)
• Temsirolimus (anticancer agent)
• Deforolimus (ridaforilimus) or AP23573
(anticancer agent)
• Adenosine Triphosphate-Competitive mTOR
Inhibitors
– AZD8055 proved to be a potent suppressor of T cell
proliferation
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17. Beneficial effects of mTOR inhibitors
in KTx
Beneficial effects Mechanism of action
Immunomodulation Prevention of T-cell proliferation, increased expression of Tregulators
Antioncogenic
activity
Inhibition of tumors caused either by overactivity of mTOR or by deficit
of PTEN. Inhibition of angiogenesis
Antiviral effects Inhibition of the signaling pathway PI3-k/Akt/mTORc1, which is used by
some herpes viruses and polyoma BK virus to replicate
Cardioprotective
effects
Inhibition of intimal proliferation. Stabilization of the atheroscerotic
plaque
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18. Different strategies with mTOR
inhibitors in kidney transplantation
Strategy Effect
Association with
standard doses
of CNI
Good prevention of rejection but low levels of creatinine clearance
Early withdrawal
of CNI
Improved renal function but increased frequency and severity of side effects.
High rate
of discontinuation. Possible increase of donor-specific antibodies
Late withdrawal
of CNI
Mild improvement of GFR, lower risk of malignancy but higher incidence of
adverse events leading to more frequent drug discontinuation.
In patients with poor GFR and/or proteinuria, the maneuver can further
deteriorate renal function
Minimization of
CNI
Good prevention of rejection, good levels of GFR-acceptable rate of adverse
events
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19. Sirolimus dosage in KTx. Initial Dose (Post-Transplant)
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• Give initial dose as soon as possible after transplantation, and 4 hours
after cyclosporine
• Once maintenance dose is adjusted, continue on the new maintenance
dose for ≥ 7-14 days before further dose adjustment
• Dosage adjustment may be based on simple proportion: New sirolimus
dose = current dose x (target concentration/current concentration)
• LD should be considered in addition to new maintenance dose when it is
necessary to increase sirolimus trough concentrations: sirolimus LD = 3 x
(new maintenance dose - current maintenance dose)
• Max Dose: 40 mg/day. If estimated dose is >40 mg/day due to addition of
LD, administer LD over 2 days; monitor trough concentrations at least 3-4
days after LD(s)

20. Sirolimus dosage in KTx. Prophylaxis of Renal
Transplant Rejection
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• Initiate with concomitant cyclosporine and corticosteroids
• Oral solution and tablets interchangeable on a mg per mg basis
• Target whole blood trough concentrations: 16-24 ng/mL for the first year
following transplantation; thereafter, 12-20 ng/mL

21. Sirolimus dosage in KTx. High immunologic Risk:
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• <40 kg: 3 mg/m² loading dose
• ≥40 kg: 15 mg PO loading dose
• Maintenance: 5 mg/day PO if >40 kg and 1 mg/m²/day if <40 kg on day 2
and thereafter; obtain trough levels between days 5 and 7
• Dose adjustments: Dose should be adjusted to maintain trough
concentrations within desired range based on clinical state and
concomitant therapy; further dose adjustment should not be done
sooner than 7-14 days following a dose adjustment

22. Sirolimus dosage in KTx. High immunologic Risk:
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• Concomitant therapy:
• For the first year, following transplantation, sirolimus should be used in
combination with cyclosporine and corticosteroids; cyclosporine may be
initiated at 7 mg/kg/day in divided doses with the dose adjusted to
achieve trough concentrations; prednisone should be given at a dose of 5
mg/day

23. Sirolimus dosage in KTx. Low-Moderate Immunologic
Risk:
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• Give LD equivalent to 3X the maintenance dose.
• Give with cyclosporine and corticosteroids; progressively discontinue
cyclosporine over 4-8 weeks at w2-4 months following transplantation.
Adjust dose to maintain blood trough concentration within target range
• Target sirolimus whole blood trough concentrations: 1st year: 16-24
ng/mL. Thereafter: 12-20 ng/mL

24. Sirolimus dosage in KTx. Low-to-moderate immunologic
Risk:
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• <40 kg: 3 mg/m² loading dose
• ≥40 kg: 6 mg PO loading dose
• Maintenance: 2 mg/day PO if ≥ 40 kg and 1 mg/m²/day if <40 kg on day 2
and thereafter; obtain trough levels between days 5 and 7
• Dose adjustments: Dose should be adjusted to maintain trough
concentrations within desired range based on clinical state and
concomitant therapy; further dose adjustment should not be done
sooner than 7-14 days following a dose adjustment

25. Sirolimus dosage in KTx. Low-to-moderate immunologic
Risk:
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• Concomitant therapy:
• Following transplantation, sirolimus should be used in combination with
cyclosporine and corticosteroids; may discontinue cyclosporine gradually
over 4-8 weeks two to four months after transplant in patients with low
immunologic risk, & sirolimus dose increased (serum concentrations of
sirolimus may decrease following cyclosporine withdrawal)

26. Everolimus dosage in KTx. Low-to-moderate
immunologic Risk:
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• Indicated for prophylaxis of organ rejection in patients with low-
moderate immunologic risk.
• Use in combination with reduced doses of cyclosporine, as well as
basiliximab and corticosteroids.
• Starting dose: 0.75 mg PO q12hr initially; adjust maintenance dose to
achieve trough whole blood concentrations of 3-8 ng/mL target range.
• Administer as soon as possible after kidney transplantation

27. Medications with important drug interactions with mTORi
Decrease Concentration Of mTORi
• CYP3A4 inducers:
– phenobarbital, carbamezepine,
phenytoine
• Echinacea
• St Johns wort
• Tocilizumab
Increase Concentration Of mTORi
• CYP3A4 inhibitors :
– protease inhibitors,
erythromycin,fluconazole
• Grapefruit juice
• Tacrolimus (topical):
– enhance the adverse effect
• ACEi
– enhance the adverse effect of ACEi
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