Sirolimus and tubular toxicity

The Feb 2010 issue of AJKD talks about a study that nicely depicts the toxicities of Sirolimus.  Since its arrival to the market for preventing rejection, it has met with resistance mostly due to its severe proteinuria.  This paper describes the toxicities of sirolimus - tubules as well as in glomerulus.  Most well know toxicity of this drug is FSGS or severe proteinuria ( sometimes collapsing variant, majority the podocytopenic type of FSGS).  Severe TMA has also been noted with sirolimus use. Most of the reports of sirolimus toxicity are in kidney transplant recipients although there have been 2 reports of proteinuria in a islet cell transplant and BMT patient who had normal kidney function prior to the drug initiation.
This was a single center study done in Switzerland.  But it was open label and randomized prospective trial comparing the tubular toxic affects and rejection outcomes in cyclosporine vs sirolimus group. There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, but the elevation in markers associated with glomerular damag and tubular damage were statistically significantly more in sirolimus group. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy.  On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy. Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy.
Small but nicely done study. Just brings to mind again the utility of sirolimus. Clinically, the KDIGO guidelines have a grade 2C suggestion to use this drug for patients with Kaposi sarcoma, along with reduction in immunosuppresion.
Image source: http://upload.wikimedia.org/wikipedia/commons/d/d4/Sirolimus1.gif