The evolving role of mycophenolate mofetil in renal transplantation.

Abstract

Mycophenolate mofetil (MMF) is an ester prodrug with higher bioavailability than the active agent, mycophenolic acid (MPA).1 MPA inhibits inosine monophosphate (IMP) dehydrogenase, an enzyme that facilitates the conversion of IMP to xanthosine monophosphate, a precursor of guanine nucleotides. This is an important step in the de novo pathway of purine nucleotide synthesis on which lymphocytes primarily depend, unlike neutrophils, for example.2 In addition, different isoforms of IMP dehydrogenase exist, and MPA is not only almost five times more potent in inhibiting the type II isoform, that is associated with stimulated rather than resting lymphocytes,3 but is also, to some extent, cell type specific.4 Thus, on theoretical grounds, MMF represents a significant improvement on the antimetabolite azathioprine the use of which is well-established in organ transplantation. MMF is effective in prolonging the survival of mouse and rat cardiac allografts,5,,6 showing an additive effect with cyclosporin, brequinar or tacrolimus.6–,9 It can also reverse rejection of rat cardiac allografts6 and prolong canine hepatic allograft survival10 as well as mouse11–,13 and rat14 pancreatic allograft survival. Finally, in a canine model, it has been shown to prolong renal allograft survival15 and reverse acute rejection.16 Rat allograft studies have reported a role in reducing ischaemia-reperfusion injury.17 An additional experimental observation of potential interest in organ transplantation is the inhibitory effect of MPA on the proliferation of human arterial smooth muscle cells in vitro . Arterial disease plays a central role in chronic graft rejection, holding out hope for additional benefit from the use of MMF.18 In vivo MMF inhibits the graft coronary artery disease of rat cardiac allografts19 and cynomologous monkey-to-baboon cardiac xenografts20 and it attenuates functional, morphological and immunohistochemical changes associated with … Dr A.N. Warrens, Renal Unit, Imperial College School of Medicine, Hammersmith Hospital, L Block, Du Cane Road, London W12 0HS. e-mail: a.warrens{at}ic.ac.uk