**6.17. Metabolism and drug interactions**

As both sirolimus and CNIs are metabolized by CYP3A enzyme pathway, concomitant use of both agents can increase exposure to sirolimus 2 to 3 fold. It is generally recommended that sirolimus be administered a few hours after CNI dosing. Similar to CNIs, it interacts with drugs that induce and block the CYP3A pathway. Sirolimus is not renally excreted so dose adjust‐ ment is not needed in renal failure. However dose adjustment is recommended in patients with hepatic dysfunction.

#### **6.18. Adverse reactions**

Sirolimus is considered to be less nephrotoxic than CNIs, however there are some unique renal side effects related to its use. Sirolimus potentiates CNI nephrotoxicity and can be tubulotoxic leading to hypomagnesemia and hypokalemia. De novo development of proteinuria, or exaggeration of preexisting proteinura is seen with conversion to sirolimus.[37] Use of sirolimus is in fact contraindicated if patient has 24 hour urine protein exceeding 1 gram/day. Sirolimus has been reported to have a direct toxic effect on podocytes. [38] [39] Sirolimus associated cast nephropathy has been reported as well. [40] Thrombotic microangiopathy has also been observed with sirolimus use, likely mediated by its inhibition of VEGF pathway. [41] The discontinuation rate of Sirolimus was as high as 30% in clinical studies due to adverse reactions. [42-44]

**6.19. Everolimus**

**6.20. Corticosteroids**

**6.21. Leflunomide**

**7. Alternative maintenance regimens**

minimized or replaced with other agents.

**7.1. Steroid withdrawal/avoidance (SAW)**

from sirolimus is its shorter half life.

There are recent studies on use of everolimus in kidney transplant recipients. [46] It is similar to sirolimus in terms of mechanism of action and side effect profile. The only major difference

Overview of Immunosuppression in Renal Transplantation

http://dx.doi.org/10.5772/54865

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Since the early 1960's, corticosteroids were used in kidney transplantation both as maintenance agents and to treat acute rejections. [47-49]. Corticosteroids down-regulate cytokine gene expression through interference with transcription. Since they are lipophilic they first trans‐ locate into cytoplasm and bind to receptors. The steroid –receptor complex then translocates to the nucleus to bind to glucocorticoid responsive elements on DNA to regulate transcription. By dampening cytokine production they blunt the immune response generated by T cells. Long-term steroid use is associated with several adverse effects including hypertension, new onset diabetes after transplantation, osteoporosis, fractures, hyperlipidemia, growth retarda‐ tion, weight gain, avascular necrosis, cataracts, cosmetic changes, depression, and psychotic behavior. With the advent of potent maintenance and induction agents the transplant com‐

Leflunomide is used for maintenance immunousppression especially in patients with BK nephropathy. [50, 51] It has both imunosuppressive properties and antiviral activity against BK. It blocks pyramidine synthesis in lymphocytes. The common adverse effects with its use are GI toxicity and neuropathy. There are no major drug interactions with leflunomide.

Different immunosuppressive strategies and protocols have evolved over time to address several major concerns with maintenance regimens. Major concerns include the long term side effects of chronic steroid use, as well as long term calcineurin nephrotoxicity which contribute to decreased long-term graft survival. Protocols that have been studied and published include steroid withdrawal and avoidance, as well as studies where calcineurin use is avoided,

Steroid withdrawal typically involves discontinuing steroids several months post transplan‐ tation whereas steroid avoidance involves no corticosteroid maintenance at all and only a brief exposure to steroids in the immediate post operative period. Studies demonstrate that early steroid withdrawal is safer than late withdrawal as late withdrawal was associated with increased risk of acute rejections. [52, 53] A recent meta-analysis of 34 randomized controlled studies using SAW regimens published by Knight et al concluded that SAW is associated with

munity is now moving more and more towards steroid sparing strategies.

Use of sirolimus is not recommended immediately after transplant surgery as sirolimus impairs wound healing (by inhibiting fibroblast proliferation). Sirolimus can increase the risk of lymphocele formation and is also associated with prolonged recovery from delayed graft function. [45]. Due to its effects on tissue repair, sirolimus is generally stopped few weeks prior to any anticipated elective surgery. Metabolic side effects of sirolimus include hyperlipidemia and hyperglycemia. Sirolimus use is also associated with non-infectious atypical pneumonitis. Bactrim is typically prescribed for one year as there are studies observing fatal pneumocystis pneumonia with sirolimus use. Sirolimus also suppresses bone marrow leading to cytopenias. Cell counts should be closely monitored especially when used in combination with MMF. Patients also can develop oral ulcers with this agent.


**Tac, Tacrolimus; CsA, Cyclosporine; mTORi, mammalian target of rapamycin inhibitor; MMF, mycophenolate mofetil ↑: mild-moderate adverse effect on the complication** Tac, Tacrolimus; CsA, Cyclosporine; mTORi, mammalian target of rapamycin inhibitor; MMF, mycophenolate mofetil

**↑↑: moderate-severe adverse effect on the complication** ↑: mild-moderate adverse effect on the complication

Table 3 pg. 14

↑↑: moderate-severe adverse effect on the complication

**Table 3.** Adverse Effects Of Maintenance Immunosuppressive agents
