Although modern immunosuppression in kidney transplantation has led to significant reductions in allograft rejection, drug-specific complications (including new-onset diabetes mellitus, hyperlipidemia and hypertension) remain a serious concern (1). In addition, cyclosporine and tacrolimus, calcineurin inhibitors (CNI) on which most protocols are based, are nephrotoxic (2). Nankivell et al. (3) suggest that histopathologic changes characteristic of chronic allograft nephropathy are virtually universal in renal allografts after 10 years of CNI maintenance, although this viewpoint is not universally accepted.
Recent studies indicate immunosuppressive regimens that include mycophenolate mofetil (MMF) may attenuate CNI-associated histopathologic changes and decline in renal function (1,4,5). MMF as a maintenance immunosuppressant has not been associated with short- or long-term negative effects on renal function, lipid and carbohydrate levels or blood pressure, sequelae that can affect graft and/or patient survival (6). When used in combination with cyclosporine, MMF was associated with less chronic allograft nephropathy than azathioprine (7) and significantly improved renal function in patients with existing chronic allograft nephropathy (8). In a retrospective study of 66 774 renal allograft recipients receiving CNI maintenance, MMF (compared to azathioprine) decreased the relative risk of chronic allograft failure by 27% (p = 0.001) (9), an outcome consistent with the more recently published histologic findings of Nankivell and colleagues (10).
Fixed-dose administration of MMF, typically 2 g/day in adults, is the standard regimen employed in renal transplantation. This dosing regimen, established in cyclosporine-treated patients, was validated in several large clinical trials (11–13) and was shown in the recent Efficacy Limiting Toxicity Elimination (ELITE)-Symphony Study (14) to provide renal function and graft survival benefits over other regimens when combined with daclizumab induction and corticosteroid/low-dose tacrolimus maintenance. Mycophenolic acid (MPA) is the active metabolite of MMF; there are known to be wide ranges in MPA exposure between patients receiving identical doses of MMF (15). The physiological basis underlying these differences is not well established, although a variety of potential contributing factors (specific ethnic status, renal and liver function and concurrent medications) have been identified (16). This interpatient variability has fueled an increasing interest in evaluating the utility of MPA exposure monitoring in clinical transplantation. In several studies, MPA area under the concentration–time curve (AUC) has been inversely correlated with the risk of an acute rejection episode in both renal and cardiac transplant recipients (17–21) with overexposure thought to increase the risk of infection and malignancy (22,23). APOMYGRE (24) was a 12-month study in which kidney transplant recipients on cyclosporine were randomized to fixed-dose MMF or to a concentration-controlled dose based on MPA AUC. Subjects in the concentration-controlled group demonstrated significantly less treatment failure (29% vs. 48%; p = 0.03) and biopsy-proven acute rejection (BPAR) (8% vs. 25%; p = 0.01) than controls, but little difference in infectious complications. In contrast, another recently published multicenter study found no advantage associated with concentration-controlled dosing of MMF (25), noting an overlap of MPA exposure among treatment groups and reluctance of investigators to implement early MMF dose adjustments required to achieve target MPA AUC exposure. The effect of concentration-controlled dosing of MMF in conjunction with CNI minimization is unknown.
Although limited (abbreviated) MPA AUC sampling to estimate full interdose AUC has been found to be useful (6,26–28), it can be labor intensive and cumbersome. Predose (or trough) level monitoring of tacrolimus and cyclosporine is common in clinical practice; a similar approach to MPA monitoring could be easily implemented. However, while MPA trough levels have been reported to be good and practical surrogates for MPA AUC, their utility has not been tested in large trials. Existing studies have been limited to relatively small numbers of patients and usually in the setting of cyclosporine coadministration (6).
The Opticept® trial compared three different dosing regimens, including both fixed and monitored dosing of MMF, as well as standard and reduced levels of CNIs, to better define the utility of trough level-based concentration-controlled regimens of MMF in facilitating a CNI-sparing regimen in clinical kidney transplantation.