This is a review about comparing mTors vs CNIs

2. Comparison of Glucose and Hemoglobin
Concentration in Transplant Patients Treated
With mTOR or Calcineurin Inhibitor
Masoumeh Mohkam
Professor od Pediatric Nephrology, SBMU, Tehran, Iran.
June 2020

3. • Calcineurin inhibitor (CNI)-based regimens are most commonly
used as maintenance regimens after kidney transplantation
because of their potent immunosuppressive activity.
• Long-term use of these agents has been associated with
significant nephrotoxicity, which may limit long-term graft and
patient’s survival.
• Mammalian target of rapamycin (mTOR) inhibitors have been
used in transplantation with the hope of minimizing
calcineurin inhibitor (CNI)-induced nephrotoxicity.

4. mTOR
• The mammalian targets of rapamycin (mTOR) inhibitors are
potent immunosuppressors used for prevention of acute
rejection after transplantation
•
• mTOR is a serine/threonine protein kinase, belonging to the
PI3K-related kinase family, playing a key role in regulating cell
growth as well as lipid and glucose metabolism.
• mTOR exists in 2 distinct large multi-protein complexes mTOR
complex 1 (mTORC1) and complex 2 (mTORC2).

5. • mTORC1, composed of 6 subunits, responds to amino acids,
stress, energy status, oxygen, and growth factors (including
insulin) and, when activated, promotes fundamental cellular
processes, including transcription, translation, protein and
lipid synthesis, cell growth/size, and cell metabolism.
• mTORC2, composed of 7 subunits including 4 common with
mTORC1, is activated by growth factors and amino acids and
regulates cell survival and migration, cell metabolism, and
cytoskeletal organization.
Laplante M. Cell. 2012;149:274–293.

6. Switching from CNI to mTOR inhibitor has multiple potential
benefits, including:
• Avoidance of CNI-induced nephrotoxicity and hypertension
• Reduction in malignancies, in particular of skin origin
Opelz G. Am J Transplant 2005; 5: 2725–2731
Euvrard S. N Engl J Med 2012; 367: 329–339

7. mTOR
mTOR inhibitors, when used as immunosuppressive
agents (sirolimus, everolimus), can induce diabetes with
an incidence which is low when used without
calcineurin inhibitors but high when used in
combination with calcineurin inhibitors
(from 11.0% to 38.1%)

8. Mechanisms by which mTOR inhibitors cause
NODAT
The exact mechanisms by which mTOR inhibitors cause NODAT have
not been clearly defined
Proposed mechanisms include:
• Impaired insulin-mediated suppression of hepatic glucose production
• Increased insulin resistance and/or direct beta cell toxicity (41–43).
• Indeed, renal transplant patients tested for insulin sensitivity before
and after conversion from a CNI to SRL had a significant reduction in
insulin sensitivity and beta cell function (44).
Syed NA. Mol Cell Biochem 2000; 211: 123–136
Barlow AD. Diabetes 2013; 62: 2674–2682.44

9. Pathophysiology of hyperglycemia induced
by mTOR inhibitors
A: mTOR inhibitors promote insulin resistance:
• by reducing the activity of the post insulin receptor signaling
proteins IRS1/2
• by inhibiting the PI3-kinase pathway and by increasing Jun N-
terminal kinase (JNK) activity which also reduces the activity of
the insulin PI-3 kinase pathway.
B: mTOR inhibitors reduce insulin secretion:
• by reducing the upregulating action of mTORC1 on insulin
secretion.
Bruno V. Transplantation 2018;102(25):S47-S49

10. IRS indicates insulin receptor substrate; PI3K, phosphoinositide 3-kinase; JNK, Jun N-terminal kinase; GSK3, glycogen
synthase kinase 3β; IGF, insulin-like growth factor.
Bruno V. Transplantation 2018 - Volume 102 - Issue 2S - p S47-S49

11. • Several clinical studies have suggested that SRL and its
analogues are associated with hyperglycemia
• The overall incidence of NODAT in post-transplant recipients is
as high as 15–30%.
Riella LV. Am J Transplant 2012; 12:1975–1982.
Ciancio G. Transplantation 2004; 77:252–258
Romagnoli G. Transplant 2006;Proc 38:1034–1036
Teutonico A. J Am Soc Nephrol 2005;16:3128–3135
Zaza G. Journal of Nephrology 2014;495–506

12. Complications of mTOR inhibitors
• New-onset diabetes after transplant (NODAT)
• Hypercholesterolemia.
• The overall RRs of NODAT associated with mTOR inhibitors
was 1.32 (95% confidence interval [CI] 0.92–1.87) compared
with CNI-based regimen.
• The overall RRs of hypercholesterolemia associated with
mTOR inhibitors was 2.15 (95% CI 1.35–3.41) compared with
CNI-based regimen.
Murakami. American Journal of Transplantation 2014; 14: 2317–2327

13. Incidence and RR of NODAT
A total of 2083 patients (mTOR inhibitors: 1179; controls: 904)
from seven RCTs.
• The incidence of NODAT in patients receiving mTOR inhibitor
was 5.5% (95% CI 3.26–9.3).
• There was no significant increase in the risk of NODAT with the
use of mTOR inhibitors compared with the controls (RR 1.32;
95% CI 0.92–1.87; p = 0.13).
• The fixed-effects model was used because there was no
significant heterogeneity (Q=3.68; p=0.72).
Murakami. American Journal of Transplantation 2014; 14: 2317–2327

14. Forest plot of relative risk (RR) of new-onset diabetes
after transplant (NODAT)
Murakami. American Journal of Transplantation 2014; 14: 2317–2327

15. Management of metabolic effects associated with
mTOR
• Because of the risk for diabetes, it is recommended, when starting a
treatment with an mTOR inhibitor, in all patients to check fasting blood
glucose every 2 weeks during the first month of treatment then every
month and HbA1c every 3 months
• and to intensify self-monitoring of blood glucose in patients with known
diabetes.
• When fasting blood glucose is more than 126 mg/dL, when plasma glucose
is more than 200 mg/dL at any time, or when HbA1c is more than 6.5%, it
is recommended to start antidiabetic treatment.
Lombard B. Cancer. 2014;101:175–183.
Busaidy NL. J Clin Oncol. 2012;30:2919–2928.

16. • Management of metabolic complications post-transplant has been of
great interest in order to reduce cardiovascular morbidity and
mortality.
• NODAT has been repeatedly reported to be an independent risk of
increased cardiovascular events (6,48).
• Screening of post-transplant NODAT using fasting plasma glucose (or
preferably OGTT) and early intervention using oral hypoglycemic
agents and/or insulin, targeting HgbA1c <7% are recommended (49).
Kasiske BL. Am J Transplant 2003; 3:178–185
Cole EH. Clin J Am Soc Nephrol 2008; 3: 814–821
Hornum M. Transpl Int 2013; 26: 1049–1060

18. Post kidney transplantation anemia
• Infections
• Graft loss and CKD
• Chronic diseases
• Iron deficiency
• Maintenance immunosuppressive drugs may have inhibitory effects
on erythropoiesis and result in PTA
• Thrombotic microangiopathy (CNIs), (mTOR) inhibitors,
including sirolimus (SRL)
T.C.H. Mix. Am J Transplant, 3 (2003), pp. 1426-1433
Reynolds JC. Am J Kidney Dis, 42 (2003), pp. 1058-1068
Afzali B. AJKD 2006;48(4):519-536

19. Hematological complications
• A total of 1301 patients (mTOR inhibitors: 648, controls: 653)
from seven RCTs were included for mean difference analysis of
Hgb level.
• Hgb was significantly lower in mTOR inhibitor group (-0.37 g/dL,
95% CI -0.67 to -0.08; p < 0.01) compared with control group.
• Leukocyte and platelet numbers were reported only in three
studies and there was no significant difference in their numbers
by mean difference analysis.
Murakami. American Journal of Transplantation 2014; 14: 2317–2327

20. Forest plots of Hemoglobin changes
Murakami. American Journal of Transplantation 2014; 14: 2317–2327

21. Anemia in mTOR compare to CNI
• Slower recovery of post-operatory hemoglobin (Hb) levels in SRL-
CsA/prednisone-treated patients compared to CsA/prednisone-
treated renal transplant recipients
• 35 % incidence of early post-transplant anemia in SRL-treated
patients versus 25 % in the CsA-treated group.
• 43 % incidence of anemia with SRL compared to 32 % in the CsA
group
Kahan BD, Transplantation 1998;66:1040–1046
Groth CG. Transplantation 1999;67(7):1036–1042
Kreis H. Transplantation 2000;69(7):1252–1260

22. • Thaunat et al. reported a decrease of Hb (mean decrease of 2.5 g
per 100 ml) in 86.9 % of patients switched from CNI-based
immunosuppression to SRL-based immunosuppression
• Several studies reported a decrease of Hb in patients switched from
CNI-based immunosuppression to SRL-based immunosuppression
• The CONVERT trial found that anemia was reported in 36.3 % of
patients converted to SRL versus 16.5 % of patients who continued
on CNI
Thaunat O. Transplantation 2005;80:1212–1219
Maiorano A. Transplantation 2006;82:908–912
Diekmann F. Am J Transplant 2004;4:1869–1875
Schena FP. Transplantation 2009;87:233–242

23. Dose relationship between mTOR and anemia
• A dose relationship between SRL and anemia development was
documented in phase III trials comparing SRL 2 mg/day with SRL
5 mg/day (24 vs. 35 %, respectively)
• 36 % incidence of anemia (SRL 2 mg/day) versus 56 % (SRL
5 mg/day) versus 16 % (placebo)
Kreis H. Transplantation 2000;69(7):1252–1260
McDonald AS. Transplantation 2001 71(2):271–280

24. Mechanisms of mTOR induced anemia
The complete molecular/biological machinery involved is not fully
understood.
• In patients treated with both SRL and EVR, anemia seems
mainly due to the anti-proliferative effect of the drug on bone
marrow progenitor cells.
• A possible direct impact on iron homeostasis.
Diekmann F. Nephrol Dial Transplant 2012; 27(2):537–541

25. A critical role for mTORC1 in erythropoiesis
and anemia
• mTORC1, a protein kinase that couples nutrient availability to cell growth.
• This screen revealed that reticulocytes show high levels of phosphorylated
ribosomal protein S6, a downstream target of mTORC1.
• mTORC1 activity in RBCs is regulated by dietary iron and that genetic
activation or inhibition of mTORC1 results in macrocytic or microcytic
anemia, respectively.
• Finally, ATP competitive mTOR inhibitors reduced RBC proliferation and
were lethal after treatment with phenylhydrazine, an inducer of hemolysis.
These results identify the mTORC1 pathway as a critical regulator of RBC
growth and proliferation and establish that perturbations in this pathway
result in anemia.
Zoncu R. Nature Reviews Molecular Cell Biology 2011 12:21–35.
Ohyashiki JH. Cancer Science 2009;100:970–977

26. Conclusion
The conversion from CNI to mTOR inhibitor in low-to-moderate risk
kidney transplant recipients was associated with significant increase in
hypercholesterolemia, acute rejection, proteinuria and anemia
Murakami. American Journal of Transplantation 2014; 14: 2317–2327
The conversion from CNI to mTOR inhibitors did not decrease the risk of
NODAT (RR 1.32; 95% CI 0.92–1.87; p = 0.13) and was actually associated
with a non-statistically significant increase in NODAT.
A meta-analysis to evaluate the risk of metabolic complications associated with
conversion from CNIs to mTOR inhibitors in post kidney transplant recipients in
contemporary immunosuppressive regimens.

27. • An increase in risk of NODAT associated with SRL was demonstrated
in a large registry study using data of the United States Renal Data
System from 1995 to 2003.
• Among 20 124 adult recipients of a first kidney transplant without
diabetes, patients treated with SRL in combination with an anti-
metabolite (MMF or Aza) were at increased risk for NODAT (hazard
ratio 1.36; 95% CI 1.09–1.69; p < 0.01), compared with patients
treated with CsA and an anti-metabolite
Johnston O. J Am Soc Nephrol 2008; 19: 1411–1418.
Given the higher incidence of BPAR (biopsy proven acute rejection) in the
mTOR inhibitor-based regimen, the use of steroids for treatment of acute
rejection could be contributing to the increased risk of NODAT in this group.
Murakami. American Journal of Transplantation 2014; 14: 2317–2327

28. ‫مداوم‬ ‫آموزش‬ ‫سواالت‬
1.‫هستند؟‬ ‫پیوند‬ ‫از‬ ‫بعد‬ ‫آنمی‬ ‫علل‬ ‫از‬ ‫کدامیک‬
‫الف‬–‫داروها‬
‫ب‬-‫پیوند‬ ‫رد‬
‫ج‬-‫آهن‬ ‫فقر‬
‫د‬-‫موارد‬ ‫همه‬
2.‫تبدیل‬CNI‫های‬ ‫مهارکننده‬ ‫به‬mTOR‫میکند؟‬ ‫کمتر‬ ‫واضحا‬ ‫را‬ ‫عوارض‬ ‫از‬ ‫کدامیک‬ ‫احتمال‬
‫الف‬-‫آنمی‬
‫ب‬-‫نفروتوکسیسیتی‬
‫ج‬-‫هیپرکلسترولمی‬
‫د‬-‫هیپرگلیسمی‬
3.‫است؟‬ ‫بیشتر‬ ‫کلیه‬ ‫پیوند‬ ‫از‬ ‫بعد‬ ‫دیابت‬ ‫بیماراحتمال‬ ‫مصرف‬ ‫در‬
‫الف‬-‫که‬ ‫بیماری‬CNI‫میکند‬ ‫دریافت‬
‫ب‬-‫کننده‬ ‫مهار‬ ‫که‬ ‫بیماری‬mTOR‫میکند‬ ‫دریافت‬
‫ج‬-‫که‬ ‫بیماری‬CNI‫کننده‬ ‫مهار‬ ‫و‬mTOR‫دریافت‬ ‫هم‬ ‫با‬ ‫را‬‫میکند‬
‫د‬-‫میکند‬ ‫دریافت‬ ‫موفتیل‬ ‫میکوفنولیت‬ ‫که‬ ‫بیماری‬.
4.‫است؟‬ ‫بیشتر‬ ‫کلیه‬ ‫پیوند‬ ‫از‬ ‫بعد‬ ‫آنمی‬ ‫احتمال‬ ‫دارو‬ ‫کدام‬ ‫مصرف‬ ‫در‬
‫الف‬-‫که‬ ‫بیماری‬CNI‫میکند‬ ‫دریافت‬
‫ب‬-‫کننده‬ ‫مهار‬ ‫که‬ ‫بیماری‬mTOR‫میکند‬ ‫دریافت‬
‫ج‬-‫بیماری‬‫که‬‫میکند‬ ‫دریافت‬ ‫استرویید‬
‫د‬-‫میکند‬ ‫دریافت‬ ‫موفتیل‬ ‫میکوفنولیت‬ ‫که‬ ‫بیماری‬.
‫سوال‬1:‫د‬
‫سوال‬2:‫ب‬
‫سوال‬3:‫ج‬
‫سوال‬4:‫ب‬