Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome

Abstract

The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5-2.5 µg/ml) or CsA (target trough level of 80-100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P<0.05), but not during the second year (P=0.36). In post hoc analysis, patients with low mycophenolic acid exposure (AUC <50 µg⋅h/ml) experienced 1.4 relapses per year compared with 0.27 relapses per year in those with high exposure (AUC>50 µg⋅h/ml; P<0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option.

Figure 1.

Diagram of patient flow through the clinical trial.

Figure 2.

Efficacy of CsA and MMF in preventing relapses in FR-SSNS patients. Kaplan–Meier survival analysis: Time without relapse (cumulative sustained remission) during treatment with CsA or MMF. (A) In the first treatment year (P<0.05, long-rank test). (B) In the second treatment year (P=0.36, long-rank test). Group A, MMF (dashed line); group B, CsA (straight line).

Figure 3.

Pharmacokinetics of MPA and efficacy. (A) MPA exposure (MPA-AUC) estimated by three-point measuring demonstrating lack of correlation between drug dosage and drug concentration in serum. (B) Rate of relapses depending on MPA-exposition: The patients are divided in two groups according to an MPA-AUC <50 µg⋅h/ml or >50 µg⋅h/ml. The number of relapses (P<0.05) and the mean MPA-AUC are significantly different between groups (P=0.0001). (C) ROC curves computed for 3-month MPA-AUC values (n=43). Diagnostic sensitivities (true positives) are calculated for each individual AUC value as the fraction of patients with a recurrence to have lower values. The corresponding diagnostic specificities (false negatives) are calculated as the fraction of patients with no recurrence to have higher values. At a cutoff of 57.1 µg⋅h/ml, the MPA-AUC has a diagnostic sensitivity of 80.0% and a diagnostic specificity of 63.0% to discriminate relapsing from nonrelapsing patients (ROC-AUC=0.68, P=0.02). (D) Kaplan–Meier survival analysis comparing the time without relapse (cumulative sustained remission) in patients with low (dashed line) and high (straight line) MPA exposure (AUC) (P=0.03, long-rank test). (E) Linear regression and confidence intervals (dotted lines) of MPA drug exposure (MPA-AUC) and MPA predose concentration (MPA-C₀).