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Comparison of Glucose and Hemoglobin Concentration in Transplant Patients Treated With mTOR or Calcineurin Inhibitor


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This is a review about comparing mTors vs CNIs

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Comparison of Glucose and Hemoglobin Concentration in Transplant Patients Treated With mTOR or Calcineurin Inhibitor

  1. 1. 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
  2. 2. • 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.
  3. 3. 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).
  4. 4. • 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.
  5. 5. 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
  6. 6. 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%)
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. • 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
  11. 11. 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
  12. 12. 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
  13. 13. Forest plot of relative risk (RR) of new-onset diabetes after transplant (NODAT) Murakami. American Journal of Transplantation 2014; 14: 2317–2327
  14. 14. 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.
  15. 15. • 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
  16. 16. 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
  17. 17. 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
  18. 18. Forest plots of Hemoglobin changes Murakami. American Journal of Transplantation 2014; 14: 2317–2327
  19. 19. 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
  20. 20. • 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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.
  25. 25. • 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
  26. 26. ‫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