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Lipid profile mtor vs cni

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This is a review of comparing lipid profile of CNI vs mTOR

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Lipid profile mtor vs cni

  1. 1. Lipid profile in renal transplant recipients mTOR Vs CNI Mitra Basiratnia , MD Ped nephrologist SUMS
  2. 2. Introduction  CVD is a major cause of morbidity in children with a functioning renal transplant  CVD begins in childhood while the patients are still clinically asymptomatic  this process is associated with traditional cardiovascular risk factors such as arterial hypertension, obesity, and dyslipidemia  dyslipidemia, which is also highly prevalent in pediatric patients with CKD as well as in renal transplant recipients,has not gained much attention in pediatric nephrology
  3. 3. Introduction  pediatric dyslipidemia is associated with an increased risk of atherosclerosis  atherosclerotic lesions are present decades before manifestation of coronary heart disease  maintenance immunosuppressive therapy is an important determinant.
  4. 4. Definition of dyslipidemia
  5. 5. Data on CERTAIN Registry  The CERTAIN Registry: web-based registry and research platform for pediatric renal transplantation in Europe  broad set of anthropometric, biochemical, disease-, and medication-related data is collected  All patients and/or their parents/guardians provided written informed consent to participate in the registry
  6. 6. Data before TX and 1,3,6,9,12 mo postTX 23 centers of ped nephrology: Germany, Italy,UK, Turkey Aged 0.5 – 25 years (CAKUT) most common(42%) 386 tx recipients PreTX 85 of 386 TC 183 of 386(47.4%) LDL-C in 91(23.6%) TG 136 of 386 (35.2%), Post TX 174 of 386 Complete data(45.1%)
  7. 7. Prevalence of dyslipidemia
  8. 8. Prevalence of dyslipidemia stratified by lipid parameters at RTx prior to engraftment, at 3 mo and at 1 y post-transplant
  9. 9. Association of potential risk factors with lipid levels  Age, BMI z-score, gender, donor source, or primary renal disease were not associated with TG, TC, and LDL-C serum concentrations.  eGFR was inversely associated with plasma levels of triglycerides but not with TC and LDL-C concentrations  Treatment with CsA or mTORi was associated with significantly higher concentrations of all lipid parameters  TAC or MPA was associated with lower level of all three parameters.
  10. 10. The potential impact of various immunosuppressive regimens on plasma lipid concentrations
  11. 11. Analysis of immunosuppressive regimens at 1 year post-transplant
  12. 12. the proportion of patients at risk stratified by immunosuppressive regimens
  13. 13. Risk of one high lipid marker n OR p-value
  14. 14.  pharmacological treatment of hypercholesterolemia in children is not recommended in KDIGO.  Despite statin therapy has been shown to reduce LDL-C in children and adolescents,lack of evidence for benefit and safety associated with its long-term use  nutrition and dietary counseling as well as lifestyle changes should be adopted according to KDIGO.  the adaptation of the immunosuppressive regimen could be one approach to reduce the cardiovascular risk in the long run
  15. 15.  multicenter, observational, matched cohort study over 4 years post-transplant  35 patients on everolimus plus low-dose cyclosporine, who were matched with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen.  Everolimus therapy was associated with with a higher percentage of arterial hypertension and more hyperlipidemia (p<0.001).
  16. 16. Mtor VS CNI
  17. 17. Mtor VS CNI  numerous studies have demonstrated dyslipidemia to occur more frequently in patients on Mtor inhibitors compared with those administered CNIs
  18. 18. mTOR Inhibition & Cardiovascular Diseases: Dyslipidemia and Atherosclerosis
  19. 19. Mtor  mTOR is a serine/threonine kinase highly conserved in all eukaryotes  master regulator of cellular growth and metabolism is found in the cell as mTORC1 and mTORC2  mTORC1 is implicated in protein synthesis and lipid metabolism as well as in cellular growth and proliferation  stimulation of mTORC1 blocks autophagy, a critical catabolic mechanism aimed at restoring cellular energy levels in times of nutrient deprivation and cellular stress
  20. 20.  The second complex (mTORC2) is responsible for cell survival and cytoskeleton organization  Rapalogs are mainly inhibitors of mTORC1 though some reports indicate that prolonged treatment could inhibit mTORC2 activity as well.
  21. 21. mTOR-mediated effects on lipid metabolism
  22. 22. mTOR Inhibition in Atherosclerosis  Atherosclerosis is a chronic disease of the arterial wall associated with inflammation and an imbalance in lipid metabolism.  Dysfunction of the endothelial layer results in the infiltration of LDL particles into the arterial wall, which in turn promotes infiltration of inflammatory cells and smooth muscle cell proliferation  Numerous reports have found that mTORC1 inhibition, either through genetic approaches or by administration of rapalogs, limits the progression of atherosclerosis
  23. 23. Rapalog-mediated mTORC1 inhibition counters AS by :  improving endothelial function  inhibiting smooth muscle cell proliferation  decreasing macrophage content in the plaque via autophagy  minimalizing monocyte recruitment from the bloodstream.  autophagy-mediated cholesterol efflux from plaque macrophages, thereby decreasing lipid accumulation in the plaque
  24. 24. These effects act together to inhibit the formation of foam cells, which play an important role in the development and progression of atherosclerosis
  25. 25.  rapalogs significantly reduces cardiac allograft vasculopathy, a condition with some similarities to atherosclerosis seen in heart transplantation  the risk of CVD is not higher in renal or liver transplantation patients receiving rapalogs despite significant dyslipidemia triggered by the treatment Watorek E, Szymczak M, Boratynska M, et al. Cardiovascular risk in kidney transplant recipients receiving mammalian target of rapamycin inhibitors. Transplant Proc. 2011;43:2967–296 McKenna GJ, Trotter JF, Klintmalm E, et al. Sirolimus and cardiovascular disease risk in liver transplantation. Transplantation. 2013;95: 215–221.
  26. 26.  a beneficial effect of rapalog-mediated mTOR inhibition on the progression of atherosclerosis despite induction of dyslipidemia  this may seem paradoxical at first sight, it should be noted that mTOR inhibition has pleiotropic antiatherosclerotic effects that could reverse dyslipidemia in the course of the disease  activation of macrophage cholesterol efflux reduces lipid accumulation in the plaque, thereby impeding atherosclerosis regardless of plasma lipid levels
  27. 27. Take home message  KTRs are at increased risk of CV morbidity and mortality, and side effects induced by immunosuppressive therapy may be a major contributor to this risk  dyslipidemia occurs more frequently in patients on Mtor inhibitors compared with those administered CNIs  beneficial effect of rapalog-mediated mTOR inhibition on the progression of atherosclerosis despite induction of dyslipidemia  KTRs at higher risk for CV events could be advantaged with both CNI minimization and mTOR inhibitor in immunosuppressive protocols.

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