Potential Benefits of Rapamycin Use in Renal Transplant Recipients

1. Potential Benefits of Rapamycin Use in Renal Transplant Recipients Reference: Edward KG, Hans JS. The potential benefits of rapamycin on renal function, tolerance, fibrosis, and malignancy following transplantation. Kidney Int. 2010;78:1075–1079.

2. An Overview on the Reports ofRapamycin Use • Over the last two decades, rapamycin has evolved as the inhibitor of the mammalian target of rapamycin (mTOR) enzyme. • Rapamycin is predominantly used as an immunosuppressant in organ transplantation, especially in kidney transplants. • Evidence-based studies suggested that rapamycin inhibits the regeneration of tubular cells as well as production of vascular endothelial cell growth factor by podocytes. • This vascular endothelial cell growth factor is important in maintaining the glomerular filtration barrier. • The development of proteinuria, in some patients as a sideeffect, could be probably as a result of inhibition of the endothelial cell growth factor. • This side effect of rapamycin can, however, be eliminated by proper monitoring and selection criteria of patients. • Comparatively, rapamycin is reported to be less nephrotoxic than calcineurin inhibitors (CNIs), as evaluated by previous studies.

3. There are other studies that demonstrated the effectiveness of this drug against renal transplant rejection when used in combination with CNIs; however, both these agents need to be used in lower doses to avoid potential severe side effects. • It is reported that there might be an increase in the rejection rate if CNIs are tapered away, although glomerular filtration rate may improve. • Therefore, it is recommended that within a year after transplantation, CNIs be replaced with mTOR inhibitors at strategic periods. • As evidenced by clinical data, this regimen would improve renal function, decrease rejection rates, and provide protection against nephropathy occurring due to chronic rejection of kidney transplants. • However, the benefits of rapamycin as monotherapy, in facilitating adequate allograft functions and also preventing rejection remain to be established. • Rapamycin is also used as an antifungal as well as a cytotoxic agent against tumor cells, as ensured in earlier studies.

4. However, mTORs are intimately integrated with other complex intracellular signaling pathways. mTOR basically is a part of two complex signaling pathways, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). • In these pathways, AKT signals to mTORC1, but AKT is actually regulated through phosphorylation of Ser473 by mTORC2. • The molecular intrigue of mTOR is depicted in figure 1.

6. There are a variety of other cytokines and growth factors that trigger the mTOR pathway. • In this multiple cellular process of mTOR, inhibition of one pathway influences the activation of the other integrated pathway. • For instance, in case of lipid metabolism, peroxisomeproliferator-activated receptor-g, which has an important role in adipogenesis and lipid accumulation, is positively affected by mTORC1. • Such complex molecular intrigue has been driving researchers to conduct future studies on the role of rapamycin and such other analogs on mTORs.

7. Potential Benefits of Rapamycin • Tumors dependent on angiogenesis as well as on mTOR for proliferation have yielded positive results on treatment with rapamycin. • As suggested by evidences, this is mainly due to the inhibition of vascular endothelial cell growth factor and its effect on the endothelial cell responses. • Rapamycin is also shown to have a potent tumor regressing action even in immunosuppressed patients, evidenced through clinical results. • Rapamycin also exerts protection against invading immune cells. • However, controversies still prevail regarding the use of rapamycin as an antitumor agent.

8. There is much concern surrounding which immunosuppressive is favorable for tolerance development in case of organ transplantation. • As rapamycin favors T-regulatory cell expansion, it is being considered as an ideal agent in tolerance induction regimens. • Another reported property of rapamycin is that it promotes T-cell tolerance by inhibiting dendritic cell maturation. • Recent publications have estimated that rapamycin is effective in reducing fibrotic processes following renal transplants by blocking mTORC1 and thus inhibiting fibroblasts and myofibroblasts proliferation. • Rapamycin also has a therapeutic effect against hepatic fibrosis as demonstrated by an experimental study on rats. • Nonetheless, more trials need to be conducted to determine the impact of rapamycin on fibrotic processes following kidney transplantation.

9. Pitfalls of Rapamycin Use inOrgan Transplantation • Despite the wide positive spectrum of effects of rapamycin, there are many cases of dropouts in clinical trials. • The reason is these patients on rapamycin therapy have encountered many side-effects including edema, oral ulcers, skin lesions, wound-healing problems following surgery, delayed allograft function, pneumonitis, anemia, and proteinuria as described earlier. • Dose reduction can resolve some of these side-effects to an extent; however, it is more likely that these side-effects may persist and eventually lead to discontinuation of rapamycin. • Management of transplant recipients with rapamycin therefore needs a thorough assessment keeping in view its risks to benefits ratio.

10. Conclusion • Many factors need to be taken into account to evaluate the future uses of rapamycin; important of these are development of tumor and fibrosis following organ transplantation, which has remained a burning issue in the field of transplantation medicine. • Based on the support from available evidence-based studies, rapamycin can be taken as the most potent immunosuppressive drug that can also be used in the prevention of fibrosis and malignancy in renal transplantation. • Rapamycin is also being tested in ongoing trials if it can suppress hepatocellular malignancy in liver transplant recipients. • However, in order to be able to gain more uses in the field of transplantation medicine, more clinical trials have to be carried out to establish that the reported positive attributes are genuine. • Furthermore, future clinical trials would definitely help physicians to better manage the sideeffects of rapamycin rather than prematurely discontinuing it. • Moreover, evidences are also required through further studies whether the benefits of rapamycin outweigh the potential risks associated with it in the management of transplant recipients.