Azathioprine nephrotoxicity

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Immunosuppressive agents such as azathioprine and mercaptopurine (a metabohte of azathioprine) are sometimes used for the treatment of IBD. These agents are generally reserved for cases that are refractory to steroids and may be associated with serious adverse effects such as lymphomas, pancreatitis, or nephrotoxicity. Cyclosporine has been of short-term benefit in acute, severe ulcerative colitis when used in a continuous infusion. 

Ciclosporin may induce remission in some patients with severe ulcerative colitis unresponsive to corticosteroid. The drug is given in a dose of 2-4 mg/kg i.v. until remission is attained. Renal function should be monitored closely as ciclosporin is nephrotoxic (see p. 620). For maintenance therapy azathioprine (see below) is often substituted. Ciclosporin use only delays surgery for many patients after 1 year 50% will have relapsed and undergone colectomy. 

A 42-year-old woman with a renal transplant taking triple immunosuppression (azathioprine, ciclosporin, and glucocorticoids) was converted after 7 years from azathioprine plus ciclosporin to mycophenolate (2 g/ day) because of ciclosporin nephrotoxicity (15). Within 2 months she had developed severe persistent watery diarrhea (5-10 stools/day) and lost 7 kg over 2 months. Investigations ruled out an infectious cause and there were features of duodenal villous atrophy on histological examination. Diarrhea disappeared after mycophenolate withdrawal and two subsequent duodenal biopsies showed improvement 2 months later and further complete recovery 6 months later. 

While CSA remarkably improved short-term graft and patient survival as compared to azathioprine-based immunosuppression, the same outcome has not been consistently demonstrated on long-term survival. One of the factors possibly related to this paradox is the role of chronic CSA nephrotoxicity in chronic allograft nephropathy. Marcen et al compared 128 CSA-treated and 185 azathioprine-treated cadaveric first renal transplant recipients followed for at least 10 years. In the first three years, post-transplant actuarial... 

There are few data about pharmacological management of chronic CSA nephrotoxicity in the clinical setting. McCulloch et al studied the effects of nifedipine in CSA-induced interstitial fibrosis in renal transplantation. The authors compared three groups of patients (conventional CSA dose versus conventional CSA dose plus nifedipine versus low CSA dose plus azathioprine) measuring baseline cortical interstitial volume fraction after one, six and 12 months of therapy. After six and 12 months interstitial volume was lower in patients treated with CSA plus nifedipine as compared with... 

Fiunt SA, Stinson EB, Oyer PE, Billingham ME, Gamberg P, Miller J, Schroeder JS, Baldwin JC, Shumway NE. Results of"immuno-conversion from cyclosporine to azathioprine in heart transplant recipients with progressive nephrotoxicity. Transplant Proc... 

Therapy typically involves a calcineurin inhibitor (e.g., cyclosporine or tacrolimus), glucocorticoids, and mycophenolate mofetil (a purine metabolism inhibitor see below), each directed at a discrete site in T-cell activation. Alternatively, sirolimus can be used to limit exposure to the nephrotoxic calcineurin inhibitors. Glucocorticoids, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, and various monoclonal and polyclonal antibodies are all approved for use in transplantation. 

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