The current status of mycophenolate mofetil in pediatric renal transplantation

Mycophenolate mofetil (MMF) is the 2-morpholinoethyl ester of the active compound mycophenolic acid (MPA). It is a prodrug that was speci®cally developed to increase the oral bioavailibility of MPA (1). MPA was ®rst isolated from a Penicillium culture. The drug was initially investigated as an antifungal and antibacterial agent but its antiviral, antitumor and immunosuppressive properties were soon discovered. At the beginning of the 1970s, MPA was studied for the treatment of refractory psoriasis and advanced malignancy (2). Interest in MPA as an immunosuppressive agent after organ transplantation was renewed by the studies of Allison and co-workers, showing that MPA blocks selectively the proliferation of T and B lymphocytes (3, 4). In contrast to cyclosporin A (CsA) and tacrolimus, both of which interfere with the early phase of lymphocyte response to antigen presentation by inhibiting cytokine synthesis by T lymphocytes, MPA has no detectable effect on interleukin-2 production in mitogen-activated peripheral blood lymphocytes. The different mode of action also explains the rationale for combining MMF with CsA or tacrolimus. MPA is a reversible, non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and guanylate synthetase, two enzymes that play a key role in the de novo purine synthesis pathway from ribose phosphate. Inhibition of both enzymes causes intracellular depletion of guanosine triphosphate (GTP) and deoxy-GTP (5). As purine synthesis in lymphocytes depends primarily on the de novo pathway, by this depletion both T and B lymphocytes are ®xed in the S phase of the cell cycle and cannot proliferate. In contrast to lymphocytes, purine synthesis in most other cells depends on both the de novo pathway and on the salvage pathway in which purine bases are phosphorylated and recycled. Therefore, the antiproliferative action of MMF should be lymphocyte-speci®c. Another reason for the preferential effect of MPA on lymphocytes is that the type II isoform of IMPDH, which predominates in proliferating lymphocytes, is four times more sensitive to the inhibition by MPA than is the type I isoform expressed in most other cells (6). Depletion of GTP not only blocks the proliferation of lymphocytes but also inhibits the transfer of fucose and mannose to glycoproteins, some of which are adhesion molecules (7). By this mechanism MPA may affect lymphocyte and monocyte recruitment into sites of in ̄ammation, such as vascular organ transplant rejection (7). This ®nding may explain the bene®cial results seen with MMF as rescue therapy for steroid-resistant rejection (8). In addition, MMF in clinically attainable concentrations also inhibits the proliferation of human smooth muscle cells, ®broblasts and endothelial cells (7), all of which may play an important role in the occurrence of chronic allograft arteriolopathy. Large-scale multicenter double-blind randomized controlled studies of oral MMF in adult renal allograft recipients have shown its effectiveness in the suppression of acute biopsyproven rejection when used in combination with standard doses of CsA and glucocorticoids. Relative to placebo (9), or azathioprine with (10) or without (11) antilymphocyte globulin induction therapy, MMF at doses of 2 or 3 g/d on a twice-daily schedule consistently reduced the incidence of acute rejection by almost 50% over the ®rst 6 months post-transplant. Although the 3 g/d dose appeared to show somewhat more effect, it was less-well tolerated than the lower dose and so overall did not offer any additional bene®t. Hence, the currently recommended dose in adult renal transplant recipients is 2 g MMF/d. Azathioprine and MMF at 2 g/d had comparable clinical safety, so the reduction in acute rejection was not gained at the expense of an increase in adverse events. MMF is generally well-tolerated except for the initial gastrointestinal effects, which may be due to a large enterohepatic Pediatr Transplantation 1999: 3: 5±9 Printed in UK. All rights reserved Copyright # Munksgaard 1999