Findings.

Compared with control subjects, the patients who were carriers for the specific UGT1A9 polymorphism showed significantly lower exposure to mycophenolic acid and lower estimated enterohepatic recycling. There was no apparent change in metabolism. Compared with the control subjects, carriers of a different UGT1A9 polymorphism, UgT1A9*3, had higher mycophenolic acid maximum concentrations. The results of this study indicate that mycophenolic acid dosage would be significantly affected by the UGT genotype of an individual. This provides at least a partial explanation for why “one size fits all” does not apply to dosing patients with MMF.

Commentary.

The information in this article, although somewhat peripheral to the day-to-day practice of nephrology, gives insight as to the complexity of mycophenolic acid exposure and thus efficacy and toxicity in individual patients. Clearly, the current practice of starting with a fixed dosage of 1 g twice daily and titrating down to the maximum dosage tolerable by adverse effects such as gastrointestinal intolerance and cytopenias is somewhat primitive. Disappointing is that simple trough level monitoring has not found much utility. Furthermore, there are differential effects of cyclosporine to block enterohepatic recycling and tacrolimus-based regimens to leave this process relatively unaffected. Area-under-the-curve monitoring is simply not practical for most transplant patients in long-term follow-up settings. Also, it is not even known whether the area under the curve is stable over time.

Having a signature genotype on the patient's drug-metabolizing enzymes might provide a useful clue to dosing initial therapy with MMF. Further studies on this approach will be forthcoming. For now, therapy with MMF will continue to be empiric. It should be recognized that patients with renal dysfunction have reduced protein binding of mycophenolic acid, leading to higher free concentration and enhanced adverse effects. Thus, nephrotic patients with low serum albumin may be at increased risk for adverse consequences, particularly cytopenias, if dosage adjustment is not made. Although studies that largely were supported by the manufacturers of MMF and the enteric-coated sodium salt have shown that reducing the dosage enhances rejection activity, none of these studies has provided a pharmacokinetic basis for these observations. The enteric-coated formula has shown no superiority in terms of efficacy or gastrointestinal adverse effects, and thus the foregoing discussion most likely applies to both drugs.

Findings.

This was an intention-to-treat study of 682 patients, 336 of whom were treated with cyclosporine microemulsion and 346 with tacrolimus. A total of 567 did not have diabetes at the baseline visit, and their risk for diabetes including steroid doses was similar at baseline. The end point was new-onset diabetes after transplantation or impaired fasting glucose at 6 mo. This was a multicenter study, and a variety of steroid protocols were used in these patients. It is pointed out by an editorialist for these articles that the dosages of steroids and target tacrolimus trough levels may be higher than is currently used in clinical practice and may partially account for the results obtained (1). The primary efficacy end point was biopsy-proven acute rejection, graft loss, or patient death at 6 mo. Renal function was estimated by the Cockcroft-Gault formula.

There was statistically more diabetes in the tacrolimus patients, 96 of whom developed the end point of new-onset diabetes or fasting glucose intolerance. This represents 33.6% of the patients. Seventy-three cyclosporine microemulsion patients achieved this end point for a 26% prevalence. Efficacy was no different between the groups with an end point occurring in 43 (12.8%) cyclosporine microemulsion patients and 34 (9.8%) tacrolimus patients. Renal function as estimated by the formula was no different. BP was no different, but total cholesterol and LDL cholesterol were higher in cyclosporine compared with tacrolimus patients. It should be noted that the study was supported financially by Novartis.

Commentary.

This large, well-done clinical study points out what has been thought by transplant physicians, namely that the price for effective immunosuppression with both calcineurin inhibitors is an increased incidence of posttransplantation diabetes, which is obviously a major risk factor for cardiovascular disease. A recent review of this subject has appeared in the pages of the Clinical Journal of the American Society of Nephrology (2). Efficacy between the two immunosuppressive drugs is similar as noticed in previous studies. The trend toward less rejection with tacrolimus is again noted. The major criticism of this study is the higher steroid burden and the trough levels and thus the increased exposure to tacrolimus provided by the protocol. Both steroids and tacrolimus cause insulin resistance, contributing to the risk for posttransplantation diabetes. Thus, the differences between the two drugs are not terribly surprising and do favor the sponsor's compounds. For the physician contemplating which calcineurin inhibitor to use, the choice should be based on individual patient factors. These include the immunologic risk of the patients versus the risk for cardiovascular and metabolic complications. Individual choices can then be rationalized. We have two effective calcineurin inhibitors, and their differences and similarities should be considered in prescribing for the individual patient.

Findings.

A total of 536 patients who were receiving their first renal transplant were randomly assigned to one of three regimens. All patients received induction with daclizumab, a CD25 mAb, mycophenolate mofetil, and corticosteroids. Withdrawal from cyclosporine starting at month 4 and completed by month 6 was given to one group, another had low-dosage cyclosporine continued but targeting a lower-than-usual trough blood level of 50 to 100 ng/ml, and a final group received a standard dosage of cyclosporine. There was significant increase in biopsy-proven acute rejection in the group that was withdrawn from cyclosporine of 38% versus the low- or standard-dosage cyclosporine groups, which were 25.4 and 27.5%, respectively. Renal function as measured by GFR was not different in all three groups. The authors concluded that maintenance of cyclosporine probably is useful in avoiding higher rejection rates and that low-dosage cyclosporine as indicated by this protocol targeting lower trough levels is safe.

Commentary.

As pointed out by the editorialists for this article, this study does document a lower level of rejection when calcineurin inhibitors are maintained versus their withdrawal at 4 to 6 mo (2). This begs the question of whether the addition of a presumably non-nephrotoxic immunosuppressive agent such as sirolimus would provide lower rates of rejection comparable to the calcineurin inhibitor arms of the study. Left unexplained is the higher-than-usual rejection rates of all groups in this study versus what is reported by other transplant centers usually experiencing 10 to 15% acute rejection rates. Deficiencies in this study are again noted by the editorialist. Cyclosporine levels in the standard arm approach the low-dosage arm, perhaps accounting for the minor differences in rejection between these two groups. The lack of effect on renal function may be due to short-term follow-up. Translation of these data to the longer term effects of calcineurin inhibitors to reduce renal function gradually over time cannot be addressed by this short-term study. It is not known whether exposure to cyclosporine in lower-than-conventional dosages is beneficial over the long haul. Also, the effect of more potent induction before calcineurin withdrawal is left up in the air. Because excellent results are obtained in renal transplantation at the present time using triple drug regimens, the standard protocols for cyclosporine and tacrolimus maintenance therapies should aim for 6-mo trough calcineurin levels between 100 and 150 and tacrolimus levels between 5 and 10. This should remain the standard of care until well-controlled, long-term clinical results are available from CAESAR or other studies.