Abstract
for long time, calcineurin-inhibitors (CNIs) was the best broadly used immunosuppressant in organ transplantation; since it had proven its efficacy in the reduction of acute rejection episodes and early graft loss, though their use in the long-term, are associated with chronic allograft nephropathy (CAN), besides it increases the cardiovascular risks such as diabetes, hypertension, and dyslipidemias. Moreover, CNIs in combination with other immunosuppressant's increases the risk of fatal infections and malignancy. Ultimately the introduction of the mammalian focus of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus in 1990s, had changed the face of transplantation and conveyed a great hope to transplant physicians as an innovative class of effective immunosuppressants with a unique mechanism and less nephrotoxic effects (1-6). In this review article we will try briefly to elicit the clinical indications, advantage and disadvantage of m-TOR inhibitors over other immunosuppressant’s medications and their clinical indications inside and outside the transplant field.
Highlights
Renal transplantation remains the best treatment approach for most patients with end-stage renal disease
Sirolimus is the prototype of the first generation of mTOR inhibitors and resemble in its structure tacrolimus structure, as it fixes to the immunophilin FK binding protein-12 (FKBP-12), to form an immunophilin complex
Pre-clinical studies had suggested a beneficial effect of mTORIs on atherosclerosis with favorable effects were found in human cardiac transplantation, in which SRL has been shown to reduce the progression of allograft vasculopathy [4]
Summary
Renal transplantation remains the best treatment approach for most patients with end-stage renal disease. Sirolimus is the prototype of the first generation of mTOR inhibitors and resemble in its structure tacrolimus structure, as it fixes to the immunophilin FK binding protein-12 (FKBP-12), to form an immunophilin complex (catalyst) The objective of this SRL-FKBP-12 complex is the serine-threonine kinase of the phosphatidyl-inositol-3-kinase pathway, which is called mTOR. The serine/threonine kinase mTOR is a downstream effector of the PI3K/AKT pathway, and forms two distinct multiprotein complexes, mTORC1 and mTORC2 (figure 1) These two complexes have a separate network of protein partners, feedback loops, substrates, and regulators [11]. Rapamune Maintenance Regimen [30] is a prospective, open-labeled, randomized, multicenter trial, included 525patients with aim to compare early conversion to SRL while watching the effect on cGFR over 24 months. Patients were followed for a median time of 519 days
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