Nahoko Yata

Effective and safe treatment with cyclosporine in nephrotic children: A prospective, randomized multicenter trial

We conducted a prospective, open-label multicenter trial to evaluate the efficacy and safety of treating children with frequently relapsing nephrotic syndrome with cyclosporine. Patients were randomly divided into two groups with both initially receiving cyclosporine for 6 months to maintain a whole-blood trough level between 80 and 100 ng/ml. Over the next 18 months, the dose was adjusted to maintain a slightly lower (60-80 ng/ml) trough level in Group A, while Group B received a fixed dose of 2.5 mg/kg/day. The primary end point was the rate of sustained remission with analysis based on the intention-to-treat principle. After 2 years, the rate of sustained remission was significantly higher while the hazard ratio for relapse was significantly lower in Group A as compared with Group B. Mild arteriolar hyalinosis of the kidney was more frequently seen in Group A than in Group B, but no patient was diagnosed with striped interstitial fibrosis or tubular atrophy. We conclude that cyclosporine given to maintain targeted trough levels is an effective and relatively safe treatment for children with frequently relapsing nephrotic syndrome.

Age, gender, and body length effects on reference serum creatinine levels determined by an enzymatic method in Japanese children : a multicenter study

BackgroundEnzymatic methods have recently been used to measure creatinine (Cr) instead of the Jaffe method. Therefore, it is necessary to determine the reference serum Cr value for these enzymatic methods to evaluate renal function in Japanese children.MethodsTo determine reference values of serum Cr in Japanese children, 1151 children (517 male, 634 female) aged between 1 month and 18 years had their serum Cr values measured by an enzymatic method. To be included in the study the children had to be without kidney disease, urogenital disease, infectious disease, inflammatory disease, dehydration, muscular disease, anomaly syndrome, cardiovascular disease, malignant disease, hypertension, liver or pancreas disease, or pregnancy.ResultsThe medians of reference values increased gradually with age, i.e., 0.30 mg/dl at 4 years old and 0.41 mg/dl at 10 years old. In adolescence, they increased significantly more rapidly in males than in females. We found a linear regression equation capable of estimating the reference value of serum Cr in children aged 2–11 years, and quintic regression equations capable of estimating the reference values of serum Cr in male and female children of all ages.ConclusionThe reference serum Cr levels determined by an enzymatic method related to age, gender, and body length, and our linear and polynomial equations showing the relationship between body length and serum Cr level will be applicable for screening of renal function in Asian as well as Japanese children.

Treatment with microemulsified cyclosporine in children with frequently relapsing nephrotic syndrome

BACKGROUND We previously established a treatment protocol for conventional cyclosporine (Sandimmune, Novartis, Basel, Switzerland) in children with frequently relapsing nephrotic syndrome; ∼50% of patients remained relapse free for 2 years, without serious adverse events. Recently, microemulsified cyclosporine (Neoral, Novartis), which has a more stable absorption profile than conventional cyclosporine, has been developed. We tested the hypothesis that microemulsified cyclosporine is at least as effective as conventional cyclosporine. METHODS To evaluate the safety and efficacy of microemulsified cyclosporine, a prospective, multicentre trial was conducted according to the previously established protocol, using microemulsified cyclosporine instead of conventional cyclosporine. The duration of treatment was 24 months. During the first 6 months, patients received microemulsified cyclosporine in a dose that maintained the trough level between 80 and 100 ng/mL of cyclosporine. For the next 18 months, the dose was adjusted to maintain a level between 60 and 80 ng/mL. RESULTS A total of 62 patients (median age, 5.4 years; 48 males, 14 females) were studied. The frequency of relapse decreased from 4.6 ± 1.4 to 0.7 ± 1.5 times per year (P < 0.0001). The probability of relapse-free survival at Month 24 was 58.1% (95% confidence interval, 45.8-70.3%). The probability of progression (to frequently relapsing nephrotic syndrome)-free survival at Month 24 was 88.5% (95% confidence interval, 80.4-96.5%). Cyclosporine nephrotoxicity was detected in only 8.6% of patients who underwent renal biopsy after 2 years of treatment. Antihypertensive agents were administered to 12.9% of the patients to control hypertension without severe sequelae. CONCLUSIONS Microemulsified cyclosporine administered according to our treatment protocol is safe and effective in children with frequently relapsing nephrotic syndrome.

Two-Year Follow-Up of a Prospective Clinical Trial of Cyclosporine for Frequently Relapsing Nephrotic Syndrome in Children

BACKGROUND AND OBJECTIVES Although the safety and efficacy of cyclosporine in children with frequently relapsing nephrotic syndrome (FRNS) have been confirmed, no prospective follow-up data on relapse after cyclosporine have appeared. This study is a prospective follow-up trial after 2-year treatment with cyclosporine to investigate cyclosporine dependency after its discontinuation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Participants who had undergone 2-year protocol treatment with microemulsified cyclosporine for FRNS between January 2000 and December 2005 were followed for an additional 2 years. The primary end point was relapse-free survival after the complete discontinuation of cyclosporine, and the secondary end point was regression-free survival (time to regression to FRNS). RESULTS After exclusion of 7 patients who showed regression to FRNS during the 2-year treatment period, 49 children (median age, 6.5 years) were followed, and classified as children without (n=32; group A) and with (n=17; group B) relapse during the initial cyclosporine treatment. Overall, relapse-free survival probability at 24 months after cyclosporine discontinuation was 15.3% and regression to FRNS-free survival probability was 40.8%. By group, the probability of relapse-free survival was significantly higher in group A (17.9%) than in group B (8.3%) (P<0.001). CONCLUSIONS Children with FRNS who receive cyclosporine are at high risk of relapse after discontinuation, particularly those who experience relapse during cyclosporine treatment.

Segmental Membranous Glomerulonephritis in Children: Comparison with Global Membranous Glomerulonephritis

Generally, idiopathic membranous glomerulonephritis (MGN) is a global glomerular disease that affects the whole of the glomerulus. However, idiopathic segmental MGN (SMGN) that shows IgG deposits in a portion of the glomerulus is encountered often. For clarification of whether SMGN is the same entity as idiopathic global MGN (GMGN), the two diseases were compared. From 1978 to 2004, 38 children (11 with SMGN and 27 with GMGN) received a diagnosis of idiopathic MGN. Immunofluorescence microscopy showed segmental granular IgG staining along the capillary loops in SMGN, whereas GMGN showed global staining. On light microscopy, SMGN showed segmental thickening of the glomerular basement membrane, with spike formation, whereas GMGN showed global lesions. The frequency of C1q deposits in SMGN was significantly higher than that in GMGN (91 versus 41%; P < 0.01). On electron microscopy, mesangial electron-dense deposits were detected in 10 (91%) cases of SMGN and also were found in the subepithelial and intramembranous area, whereas only six (22%) cases of GMGN had mesangial electron-dense deposits (P < 0.001). There were no significant differences in clinical features between the groups. Two children with SMGN underwent a repeat biopsy 3 yr after the first biopsy, and both patients again showed SMGN. At the final observation (mean observation time 7.5 yr in SMGN and 12.4 yr in GMGN), all children of both groups had a good outcome. In conclusion, these findings as a whole suggest that SMGN may be another glomerular disease entity with child predominance that is distinctive from GMGN.

Cyclosporine C2 Monitoring for the Treatment of Frequently Relapsing Nephrotic Syndrome in Children: A Multicenter Randomized Phase II Trial

BACKGROUND AND OBJECTIVES An open-label, multicenter, randomized phase II trial was conducted from July 1, 2005 to March 29, 2011 to compare two protocols for treating children with frequently relapsing nephrotic syndrome using microemulsified cyclosporine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Ninety-three children with frequently relapsing nephrotic syndrome were randomly assigned to group A (n=46) or group B (n=47). In both groups, the 2-hour postdose cyclosporine level was monitored. For group A, the cyclosporine target was set to 600-700 ng/ml for the first 6 months and 450-550 ng/ml for the next 18 months; for group B, it was set to 450-550 ng/ml for the first 6 months and 300-400 ng/ml for the next 18 months. The primary end point was the sustained remission rate. At the end of the study, if there was no difference in safety profile between the two groups and the sustained remission rate in group A was superior to group B with a decision threshold of 8%, then the regimen for group A would be determined the better treatment. RESULTS Eight children from an ineligible institution, where cyclosporine levels were not measured, were excluded from all analyses. At 24 months, the sustained remission rate was nonsignificantly higher in group A (n=43) than group B (n=42; 64.4% versus 50.0%; hazard ratio, 0.57; 95% confidence interval, 0.29 to 1.11; P=0.09), and the progression-free survival rate was significantly higher (88.1% versus 68.4%; hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.94; P=0.03). The relapse rate was significantly lower in group A than group B (0.41 versus 0.95 times/person-year; hazard ratio, 0.43; 95% confidence interval, 0.19 to 0.84; P=0.02). The rate and severity of adverse events were similar in both treatment groups. CONCLUSION The sustained remission rate was not significantly different between the two treatment groups, but the regimen with the higher 2-hour postdose cyclosporine level target improved progression-free survival and reduced the relapse rate.