mTOR inhibitors like sirolimus and everolimus are immunosuppressants that provide an alternative to calcineurin inhibitors for renal transplant patients. They have antiproliferative properties, cause less nephrotoxicity than CNIs, and are associated with lower rates of malignancy, viral infections, and improved renal function when used to convert patients from a CNI-based regimen. However, mTOR inhibitors are less effective at preventing acute rejection when used without a CNI in de novo transplants.

1. mTOR
inhibitors in
renal
transplant

2. LIMITATIONS WITH IMMUNOSUPPRESANTS
 One-year patient survival can be expected to be above 90 % as well as 1-
year graft survival.
 Usually, 1-year acute rejection rates are observed to be between 5 and 15 %
in a therapy based on calcineurin-inhibitors (CNI),mycophenolate Mofetil
or mycophenolate sodium (MMF/MPA) and steroids.
 The above-mentioned immunosuppressive regimens based on a CNI and
MMF, however, are associated with adverse events such as direct
nephrotoxicity, worsening of several cardiovascular risk factors, a higher
incidence of post-transplant cancer as well as a high incidence of viral
infections such as CMV, BKV and oncogenic viruses.
Diekmann and Campistol Transplantation Research 2015,

3. LIMITATIONS WITH CALCINEURIN INHIBITORS
 The calcineurin inhibitor drugs (CNI) are the mainstays of modern
immunosuppression in renal transplantation, but they contribute
significantly to the chronic graft loss and the high morbidity and mortality
in this population for their deleterious effects on renal graft,
cardiovascular profile and malignancies.
 Calcineurin inhibitors have reduced acute rejection rates and improved
short-term graft survival, but they cause nephrotoxicity and death with a
functioning graft.

4. RATIONALE OF USING mTOR INHIBITORS
IN RENAL TRANSPLANTATION
 Conversion from a CNI based to an mTOR-inhibitor-based regimen
has been successful at improving renal function for a number of
years after conversion
 mTor inhibitors have antiproliferative and anti-angiogenic effects
with no nephrotoxicity.
Nefrologia 2012;32(5):631-8

5. RATIONALE OF USING mTOR INHIBITORS
IN RENAL TRANSPLANTATION
 These properties could improve patient and graft long-term survival
rates in transplant recipients.
 Safest and most effective time to convert is between 1 and 6 months
after transplant.
 In addition, mtor-inhibitor-based regimens have been shown to be
associated with lower rates of post-transplant malignancy and less
cytomegalovirus infection, which may add further to the appeal of this
approach.

6. MAMMALIAN TARGET OF RAPAMYCIN (mTOR)
 TOR transduces signals that initiate synthesis of ribosomal proteins,
translation of a specific subset of messenger RNA (mRNA)
transcripts, and generation of cyclin-dependent kinases, promoting
the progression of the cell cycle. (G1 to S phase)
 This results in activation and proliferation of T and B cells and
antibody production, as well as proliferation of such nonimmune
cells as fibroblasts, endothelial cells, hepatocytes, and smooth
muscle cells.

7. mTOR inhibitors
 Sirolimus
 Everolimus
 Tedsirolimus
 Ridaforolimus

8. mTOR INHIBITORS-SIROLIMUS AND
EVEROLIMUS
 Sirolimus - A lipophilic agent & A fermentation product of streptomyces
hygroscopicus
 1970 – First investigated as anti fungal agent
 1971 – Immunosuppressive effect observed – Tacrolimus & Sirolimus share
structural similarity
 1991 – 2-Hydroxyl ethyl chain substitution of sirolimus – evorolimus was
introduced which has better bioavailability
 1999 – FDA approved Sirolimus
 2010- FDA approved everolimus

9. MECHANISM OF ACTION
 Mtor inhibitors (sirolimus, everolimus) resembles to
Tacrolimus but binds to same intracellular FK binding
proteins.
 However, whereas Tacrolimus and cyclosporine block
IL-2 gene transcription, sirolimus acts later to block
IL-2 dependent lymphocyte proliferation.
 This blockade is likely due to inhibition of
mammalian kinase, an enzyme which is essential for
cell cycle progression.
 Therefore the drug inhibits substantially T and B cell
proliferation.

12. SIROLIMUS USE
For the prophylaxis of organ rejection in patients aged ≥13 years
receiving renal transplants.
Patients at low-to moderate-immunologic risk: Use initially with
cyclosporine (CsA) and corticosteroids. CsA withdrawal is
recommended 2 to 4 months after transplantation.
Patients at high-immunologic risk: Use in combination with CsA and
corticosteroids for the first 12 months following transplantation.

13. SIROLIMUS-DOSAGE IN ADULTS (0.5 mg)
 Take once daily by mouth, consistently with or without food. Take the initial dose as soon as
possible after transplantation and 4 hours after CsA. Adjust the sirolimus maintenance dose to
achieve sirolimus trough concentrations within the target-range (5-15 ng/ml).
Patients at low- to moderate-immunologic risk
 Sirolimus and Cyclosporine Combination Therapy: One loading dose of 6 mg on day 1, followed by
daily maintenance doses of 2 mg.
 Sirolimus Following Cyclosporine Withdrawal: 2 to 4 months post-transplantation, withdraw CsA
over 4 to 8 weeks
Patients at high-immunologic risk
 Sirolimus and Cyclosporine Combination Therapy (for the first 12 months post-transplantation):
One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg

14. SIROLIMUS DOSE IN PEDIATRICS
 Children (13 years old and older, and body weight less than 40
kg): Sirolimus loading dose is 3 mg/m2 PO for 1 dose. Initial
maintenance dose is 1 mg/m2/day PO divided every 12 hours or
once daily. Adjust dose to achieve target sirolimus blood
concentration.
 Pediatric patients with body weight greater than 40 kg: Loading
dose is 6 mg PO for 1 dose and then maintenance dose 2 mg PO
once daily. Adjust dose to achieve target sirolimus blood
concentration.

15. SIROLIMUS IN RENAL
TRANSPLANTATION
 Transplant patients are at particular risk of skin tumors including
squamous cell carcinoma, Kaposi sarcoma and the group of post-
transplant lymphoproliferative diseases.
 Preliminary clinical studies have reported a lower incidence of skin
malignancy in patients treated with sirolimus compared with
cyclosporine at the time of transplantation.
 Patients receiving sirolimus without cyclosporine or sirolimus
maintenance therapy after early cyclosporine withdrawal have lower
rates of malignancy in the first 2 years after renal transplantation

16. EVEROLIMUS
 Everolimus is a sirolimus-derivative with a much shorter half-life
that recently received FDA approval for renal transplantation.
 Everolimus is also approved for treatment of advanced renal cell
cancer, subependymal giant cell astrocytoma and unresectable
pancreatic neuroendocrine tumors.
 Later it was approved for transplant indications.

17. EVEROLIMUS USE
Everolimus is a mTor inhibitor immunosuppressant indicated for
the prophylaxis of organ rejection in adult patients:
• Kidney transplant: at low-moderate immunologic risk. Use in
combination with basiliximab, cyclosporine (reduced doses)
and corticosteroids.
• Liver transplant: Administer no earlier than 30 days
posttransplant. Use in combination with tacrolimus (reduced
doses) and corticosteroids.

18. EVEROLIMUS DOSE
Available as 0.25 mg, 0.5 mg, and 0.75 mg tablets
• Kidney transplantation: starting oral dose of 0.75 mg twice daily
as soon as possible after transplantation.
• Liver transplantation: starting oral dose of 1.0 mg twice daily
starting 30 days after transplantation.
• Monitor everolimus concentrations: Adjust maintenance dose to
achieve trough concentrations within the 3-8 ng/mL target range
• Administer consistently with or without food at the same time as
cyclosporine or tacrolimus

19. LIMITATIONS OF EVEROLIMUS
Safety and efficacy has not been established in the following:
 Kidney transplant patients at high immunologic risk
 Recipients of transplanted organs other than kidney or liver
 Pediatric patients (less than 18 years)

20. CLINICAL EVIDENCES ON EVEROLIMUS
 When the association of everolimus-cyclosporine with mycophenolic-cyclosporin is
compared, imTOR allows a reduction of the calcineurin inhibitors of 60%, a better GFR
and lower proteinuria.
 A recent meta-analysis reports a greater benefit of the minimization of calcineurin
inhibitors when performed before the 6th months post-transplant, with better GFR
and with a lower risk of graft loss

21. KEY CHARACTERISTICS OF mTOR
INHIBITORS IN RENAL TRANSPLANT
 Ability to prevent renal graft dysfunction through mechanisms mediated
by mTOR, such as reducing the glomerular hypertrophy, proinflammatory
and profibrotic cytokines, or the inhibition of the transition from
epithelium to mesenchyme;
 Reduction of angiogenesis;
 Reduction of tumor growth and appearance of de novo neoplasms ;
 Reduction of viral infections by increasing the specific capacity of CD8 + T
lymphocytes against pathogens, such as CMV, in the immediate post-
transplant. Nephrology (Madr.) 2017; 37: 253-66

22. EFFECT OF mTOR INHIBITORS ON
CARDIOVASCULAR DISEASE
Conversion from CNI-based to mTOR inhibitor- based
immunosuppression has been shown to improve blood pressure
and may achieve regression of left ventricular hyperplasia.
Russ Transplantation Research 2013, 2(Suppl 1):S4

23. ADVERSE EFFECTS
 Arthralgia,
 Hirsutism,
 Diarrhoea,
 Hypertension,
 Hypokalemia,
 Rash,
 Tachycardia
 Lymphocele,
 Peripheral edema, and some
infections.
 Dose related increases in
triglycerides and cholesterol
and decreases in platelets
and hemoglobin

25. Diekmann and Campistol Transplantation Research 2015, 4(Suppl 1):5

29.  mTOR inhibitors are a safe alternative to standard immunosuppression therapy with CNI and
mycophenolate/azathioprine.
 Mild adverse events can be easily managed with an increased awareness and close
monitoring of trough levels.
 Most serious side effects are dose- and organ-dependent.
 In kidney and heart transplantation mTOR inhibitors may be safely used as either low-dose
de novo or through early-conversion.
 In the liver, conversion 4 weeks post-transplantation may reduce long-term chronic kidney
disease secondary to calcineurin nephrotoxicity, without increasing hepatic artery/portal
vein thrombosis.
Safety of mtor inhibitors in solid organ transplant
Expert Opin Drug Saf. 2016;15(3):303-19

30. LIMITATIONS
 Less efficacious with respect to rejection prophylaxis and their
use in the de novo transplant is not recommended.
 Dyslipidaemia has been found to be more prevalent in patients
converted to mTOR-inhibitor-based regimens, with increased
levels of cholesterol and triglycerides, and an increased use of
lipid-lowering agents
 High intraindividual and interindividual differences of dosing
requirements.
Russ Transplantation Research 2013, 2(Suppl 1):S4
Diekmann and Campistol Transplantation Research 2015, 4(Suppl 1):5

31. LIMITATIONS
 The use anti-mTOR in de novo transplantation without a CNI
leads to a greater risk of rejection and surgical wound
complications after TX.
 Anti-mTOR drugs can increase the risk of post- TX diabetes,
especially in predisposed individuals.

32. SUMMARY
 The initial combination of low doses of an anti-mTOR and a CNI
provides acceptable short term immune protection
 Reduced development of chronic damage to the graft mediated by
CNI
 The early conversion from a CNI to SRL/EVE may, at least, offer stable
renal function.
 Lower incidence of post-transplant malignancy
 Lower rate of viral disease after transplantation
Russ Transplantation Research 2013, 2(Suppl 1):S4