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

1. Lipid profile in renal transplant
recipients
mTOR Vs CNI
Mitra Basiratnia , MD
Ped nephrologist
SUMS

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. 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. Definition of dyslipidemia

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

7. 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%)

9. Prevalence of dyslipidemia

10. Prevalence of dyslipidemia stratified by lipid parameters at
RTx prior to engraftment, at 3 mo and at 1 y post-transplant

11. 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.

12. The potential impact of various
immunosuppressive regimens on
plasma lipid concentrations

13. Analysis of immunosuppressive regimens at
1 year post-transplant

14. the proportion of patients at risk stratified by
immunosuppressive regimens

15. Risk of one high lipid marker
n OR p-value

16.  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

17.  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).

18. Mtor VS CNI

19. Mtor VS CNI
 numerous studies have demonstrated dyslipidemia to occur more frequently in
patients on Mtor inhibitors compared with those administered CNIs

20. mTOR Inhibition & Cardiovascular
Diseases: Dyslipidemia and
Atherosclerosis

21. 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

22.  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.

23. mTOR-mediated effects on lipid metabolism

24. 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

25. 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

26. These effects act together to inhibit
the formation of foam cells, which play
an important role in the development and
progression of atherosclerosis

27.  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.

28.  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

29. 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.