**6.10. Toxicity**

The main dose limiting toxicity of MMF or enteric coated MPA is related to gastrointestinal (GI) side effects. More than one third of patients develop diarrhea and in addition some patients have nonspecific GI intolerance in the form of dyspepsia, nausea and vomiting. Indeed, there is evidence demonstrating a correlation between drug exposure and GI toxicity. [31] Most of these side effects are handled with either dose reduction or splitting the dose into 3 to 4 divided doses. Although patients may tolerate enteric coated MPA better, studies curiously do not demonstrate major differences in the GI side effect profile of MMF and enteric coated MPA. [34]

The unique antitumoral properties of sirolimus, however, make it an attractive option for im‐ munosuppression in patients with post transplant malignancies. Recent study reported by Eu‐ vrard et al (Tumorapa study) has shown that sirolimus conversion has provided protection against recurrence of skin cancers in patients with squamous cell carcinomas of the skin post

Overview of Immunosuppression in Renal Transplantation

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

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Similar to CNIs sirolimus binds to cytoplasmic protein FKBP-12 to mediate its action. The sirolimus/FKBP-12 complex then inhibits mTOR (mammalian target of rapamune). This en‐ zyme is a kinase that plays a key role in cell cycle progression (G1-S transition). Blocking mTOR has a profound effect on inhibiting T-cell proliferation and expansion. mTOR is ex‐ pressed ubiquitously so the antiproliferative effects of sirolimus is not limited to lympho‐

The anti-tumor effect of sirolimus is mediated by inhibiting the PI3K-AKT pathway which plays a critical role in cell proliferation, survival, migration and angiogenesis. [36] In addi‐ tion it inhibits growth of endothelial cells and tumor angiogenesis by interfering with syn‐

Sirolimus has a long half life of 60 to 70 hours so consideration is needed when initiating the drug or making dose adjustments. Usually patients receive a loading dose of 3-15mg fol‐ lowed by once daily dosing of 1-5mg per day. The loading and maintenance dose are gener‐ ally determined by patient weight and immunologic risk. The dose is then adjusted based on drug levels. Therapeutic drug monitoring is routinely used with sirolimus. It is recom‐ mended to check 24 hour trough levels several days after initiation or dosage adjustment of

The drug is available as oral tablet at 0.5mg, 1mg and 2mgs dose. In addition there is also liquid formulation with strength of 1mg/ml. It is metabolized by CYP3A and hence dose needs to be

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

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

cytes and attributes to several adverse effects of the drug which are detailed below.

transplant. [35]

**6.16. Clinical use**

**6.15. Mechanism of action**

thesis of vascular endothelial growth factor.

sirolimus since it takes longer to achieve a steady state.

adjusted in liver disease, but not in renal impairment.

**6.17. Metabolism and drug interactions**

with hepatic dysfunction.

**6.18. Adverse reactions**

Another major side effect of these preparations is bone marrow suppression mainly manifest‐ ing with leucopenia. Typically the dose of MMF is reduced based on the severity of leucopenia. There appears to be a correlation between the incidence of leucopenia and drug exposure. [31] Anemia and thrombocytopenia can occur as well.

#### **6.11. Azathioprine**

Azathioprine (Imuran) has been in use in transplantation for more than three decades. With introduction of CNIs and MMF, many centers have moved away from using azathioprine as a first line maintenance agent. SRTR reports from 2009 demonstrate that only 0.6% of the kidney transplant recipients were on Azathioprine. It is commonly used now primarily in patients who are intolerant to MMF. Usual daily dose administered is 2-3 mg/kg once daily.

#### **6.12. Mechanism of action, metabolism and major drug interactions**

Azathioprine is an antimetabolite a derivative of 6-mercaptopurine. It gets incorporated into cellular deoxyribonucleic acid (DNA). Once incorporated into DNA it interferes with tran‐ scription, purine and ribonucleic acid (RNA) synthesis which are important for T cell activa‐ tion. Azathioprine is metabolized by xanthine oxidase inhibitor to 6–thiouric acid. Hence allopurinol which is a xanthine oxidase inhibitor should be used with great caution with azathioprine as it can lead to significant toxicity. Typically the dose of azathioprine is reduced when used in combination with allopurinol.

#### **6.13. Adverse drug reactions**

The single most severe toxicity of azathioprine is related to suppression of bone marrow. Patients can develop profound leucopenia and thrombocytopenia. It is recommended to monitor white count and platelet count carefully every 2 weeks at initiation. The dose of the drug will need to be decreased if leucopenia occurs and severe leucopenia might necessitate discontinuation of the drug. Cholestasis, hepatic veno occlusive disease, hepatitis and rare cases of pancreatitis have been described with azathioprine use.

#### **6.14. Sirolimus**

Sirolimus (Rapamycin) was introduced to transplantation in the late 1990s. It has antitumor, antiproliferative and immunosuppressive actions. Sirolimus plays a key role in immunosup‐ pression especially as an alternative to CNIs to minimize long term CNI induced nephrotox‐ icity. SRTR database reported that the use of sirolimus as part of initial maintenance regimen peaked in 2001; however it gradually declined to only 3% of kidney transplant recipients receiving it in 2009. In the same report at 1 year post transplantation, 6.5% of recipients were receiving sirolimus. The declining use of sirolimus can be attributed to the side effects encountered with medication usage.

The unique antitumoral properties of sirolimus, however, make it an attractive option for im‐ munosuppression in patients with post transplant malignancies. Recent study reported by Eu‐ vrard et al (Tumorapa study) has shown that sirolimus conversion has provided protection against recurrence of skin cancers in patients with squamous cell carcinomas of the skin post transplant. [35]
