Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: benefits and risks.

Chronic allograft nephropathy (CAN) is the most prevalent cause of late kidney transplant failure characterized by progressive loss of graft function in combination with proteinuria and hypertension [1]. Both immunological and non-immunological factors play a role in the development of CAN, and calcineurin inhibitor (CNI) therapy has been identified to be an important non-immunological cause [2–5]. In this context, Nankivell et al. [5] demonstrated in a protocol biopsy study that at least grade I CAN could be diagnosed in all biopsy specimens 3 years after transplantation, and that histological signs of chronic CNI nephrotoxicity are omnipresent after 10 years. Sirolimus (SRL) is a new, potent, non-nephrotoxic immunosuppressive agent that possesses antiproliferative properties and exerts anti-tumour activity by various mechanisms [6–8]. In a large multicentre study, elimination of cyclosporine A (CsA) after 3 months from a protocol containing SRL and CsA was proven to be beneficial in terms of better renal function, improved renal histology and graft survival [9,10]. Moreover, a single centre study comparing de novo CsA-based immunosuppression with a de novo SRLbased protocol shows better renal function and less CAN 2 years after transplantation [11]. In light of these first positive results and given the proliferative processes predominant in CAN, conversion from a nephrotoxic to a non-nephrotoxic and antiproliferative drug like SRL might be a useful approach for prevention or treatment of CAN. So far, conversion from nephrotoxic to non-nephrotoxic regimens such as combinations of azathioprin (AZA) or mycophenolate mofetil (MMF) with steroids had been associated with a higher relative risk of acute rejection after conversion in some studies [12,13]. Another study of conversion to a regimen based on MMF, however, demonstrated no acute rejection at all [14]. In most of these studies the conversion led to better renal function after relatively short follow-up periods; however, according to a meta-analysis by Kasiske et al. [15] no benefit in terms of relative risk of long-term graft failure was achieved comparing the groups with CsA withdrawal with those of continued use of CsA. Therefore, the potent immunosuppressive, antiproliferative drug SRL, that does not show CNI-like nephrotoxicity, gave hope for a new alternative in treatment or prevention of CAN. To the authors’ knowledge, no study has been published so far that directly compares the impact of conversion to a SRL-based regimen with that of conversion to aMMF-based protocol. Therefore, in the absence of this data the authors neither intend nor are they able to favour conversion to one CNI-free protocol over the other as a general strategy. They rather intend to describe the conversion to SRL as an additional option.