Mayumi Sako

Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial

BACKGROUND Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity. METHODS We did a multicentre, double-blind, randomised, placebo-controlled trial at nine centres in Japan. We screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1-18 years. Patients with complicated FRNS or SDNS who met all other criteria were eligible for inclusion after remission of the relapse at screening. We used a computer-generated sequence to randomly assign patients (1:1) to receive rituximab (375 mg/m(2)) or placebo once weekly for 4 weeks, with age, institution, treatment history, and the intervals between the previous three relapses as adjustment factors. Patients, guardians, caregivers, physicians, and individuals assessing outcomes were masked to assignments. All patients received standard steroid treatment for the relapse at screening and stopped taking immunosuppressive agents by 169 days after randomisation. Patients were followed up for 1 year. The primary endpoint was the relapse-free period. Safety endpoints were frequency and severity of adverse events. Patients who received their assigned intervention were included in analyses. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000001405. FINDINGS Patients were centrally registered between Nov 13, 2008, and May 19, 2010. Of 52 patients who underwent randomisation, 48 received the assigned intervention (24 were given rituximab and 24 placebo). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223-374) than in the placebo group (101 days, 70-155; hazard ratio: 0·27, 0·14-0·53; p<0·0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p=0·36). INTERPRETATION Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS. FUNDING Japanese Ministry of Health, Labour and Welfare.

A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment

In this multicenter, open-label, randomized controlled trial, we determined whether 2-month prednisolone therapy for steroid-sensitive nephrotic syndrome was inferior or not to 6-month therapy despite significantly less steroid exposure. The primary end point was time from start of initial treatment to start of frequently relapsing nephrotic syndrome. The pre-specified non-inferiority margin was a hazard ratio of 1.3 with one-sided significance of 5%. We randomly assigned 255 children with an initial episode of steroid-sensitive nephrotic syndrome to either 2 - or 6-month treatment of which 246 were eligible for final analysis. The total prednisolone exposure counted both initial and relapse prednisolone treatment administered over 24 months. Median follow-up in months was 36.7 in the 2-month and 38.2 in the 6-month treatment group. Time to frequent relaps was similar in both groups; however, the median was reached only in the 6-month group (799 days). The hazard ratio was 0.86 (90% confidence interval, 0.64–1.16) and met the non-inferior margin. Time to first relapse was also similar in both groups: median day 242 (2-month) and 243 (6-month). Frequency and severity of adverse events were similar in both groups. Most adverse events were transient and occurred during initial or relapse therapy. Thus, 2 months of initial prednisolone therapy for steroid-sensitive nephrotic syndrome, despite less prednisolone exposure, is not inferior to 6 months of initial therapy in terms of time to onset of frequently relapsing nephrotic syndrome.

Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome

BackgroundRituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome.MethodsWe retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan.ResultsSeventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX (P = 0.006; hazard ratio = 0.2). Among the SRNS patients, complete (n = 6) and partial remission (n = 6) were achieved. No life-threatening adverse events were experienced.ConclusionsAlthough this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse.

Long-Term Results of a Randomized Controlled Trial in Childhood IgA Nephropathy

BACKGROUND AND OBJECTIVES Children with IgA nephropathy showing diffuse (>80%) mesangial proliferation are at high risk for end-stage renal failure (ESRF). A previous controlled trial showed that combination therapy consisting of prednisolone, azathioprine, heparin-warfarin, and dipyridamole early in the course of disease reduces immunologic renal injury and prevents the progression of sclerosed glomeruli. The objective of this study was to evaluate the long-term effectiveness of combination therapy in children with IgA nephropathy showing diffuse mesangial proliferation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A secondary analysis of a multicenter, randomized, controlled trial involving 78 children with IgA nephropathy who received either 2-year combination therapy or heparin-warfarin and dipyridamole (control) therapy was conducted. RESULTS The median duration of observation was 10 years (range, 0.5 to 18). Two of 40 patients (5%) who received combination therapy and five of 34 patients (14.7%) who received control therapy developed ESRF. A Kaplan-Meier plot of renal survival showed that the outcomes of patients in the combined therapy group were better than those in the control therapy group (log-rank P = 0.03). The 10-year renal survival probability of each group was 97.1% (95% confidence interval, 81.4 to 99.6%) and 84.8% (95% confidence interval, 55.4 to 95.5%), respectively. The Cox proportional hazards model showed that the 2-year combination therapy was significantly associated with renal survival in both univariate and multivariate analyses. CONCLUSIONS Two-year combination therapy not only ameliorated the activity of the acute phase of nephritis but also improved the long-term outcome of severe childhood IgA nephropathy.

Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease

In polycystic kidney disease (PKD), cyst lining cells show polarity abnormalities. Recent studies have demonstrated loss of cell contact in cyst cells, suggesting induction of epithelial-to-mesenchymal transition (EMT). Recently, EMT has been implicated in the pathogenesis of PKD. To explore further evidence of EMT in PKD, we examined age- and segment-specific expression of adhesion molecules and mesenchymal markers in PCK rats, an orthologous model of human autosomal-recessive PKD. Kidneys from 5 male PCK and 5 control rats each at 0 days, 1, 3, 10, and 14 wk, and 4 mo of age were serially sectioned and stained with segment-specific markers and antibodies against E-cadherin, Snail1, β-catenin, and N-cadherin. mRNAs for E-cadherin and Snail1 were quantified by real-time PCR. Vimentin, fibronectin, and α-smooth muscle actin (α-SMA) expressions were assessed as mesenchymal markers. E-cadherin expression pattern was correlated with the disease pathology in that tubule segments showing the highest expression in control had much severer cyst formation in PCK rats. In PCK rats, E-cadherin and β-catenin in cystic tubules was attenuated and localized to lateral areas of cell-cell contact, whereas nuclear expression of Snail1 increased in parallel with cyst enlargement. Some epithelial cells in large cysts derived from these segments, especially in adjacent fibrotic areas, showed positive immunoreactivity for vimentin and fibronectin. In conclusion, these findings suggest that epithelial cells in cysts acquire mesenchymal features in response to cyst enlargement and participate in progressive renal fibrosis. Our study clarified the nephron segment-specific cyst profile related to EMT in PCK rats. EMT may play a key role in polycystic kidney disease.

Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: general therapy

Nephrotic syndrome is a disorder characterized by severe proteinuria, hypoproteinemia, and generalized edema resulting from damage to the glomerular basement membrane. In Western countries, nephrotic syndrome affects 2 of 100,000 children per year [1]. In Japan, approximately 1,300 new cases per year of pediatric nephrotic syndrome are reported to the Medical Aid for Specific Chronic Disease of Children and the disease develops in 5 of 100,000 children per year. Approximately 90 % of the cases of pediatric nephrotic syndrome are idiopathic, or of unknown cause. The first-line treatment for an initial episode of pediatric idiopathic nephrotic syndrome is oral steroid therapy, which leads to remission in approximately 80 % of cases (steroidsensitive nephrotic syndrome) [2]. However, 80 % of children with steroid-sensitive nephrotic syndrome experience one or more relapses, [3] and 50 % of these children have frequent relapses [4]. Those with frequently relapsing nephrotic syndrome are prone to suffer steroid-induced side effects such as obesity, growth impairment, hypertension, diabetes mellitus, osteoporosis, and adrenal insufficiency. Many cases of steroid-resistant nephrotic syndrome, where steroids are ineffective, progress to renal failure. Pediatric idiopathic nephrotic syndrome is a very important disease in the field of pediatric nephrology. The Scientific Committee in the Japanese Society for Pediatric Nephrology previously published the ‘‘Clinical Practice Guideline for Pediatric Idiopathic Nephrotic Syndrome’’ (2013). This is the English translation from the ‘‘Medical Therapy’’ portion of the guideline.Nephrotic syndrome is a disorder characterized by severe proteinuria, hypoproteinemia, and generalized edema resulting from damage to the glomerular basement membrane. In Western countries, nephrotic syndrome affects 2 of 100,000 children per year [1]. In Japan, approximately 1,300 new cases per year of pediatric nephrotic syndrome are reported to the Medical Aid for Specific Chronic Disease of Children and the disease develops in 5 of 100,000 children per year. Approximately 90 % of the cases of pediatric nephrotic syndrome are idiopathic, or of unknown cause. The first-line treatment for an initial episode of pediatric idiopathic nephrotic syndrome is oral steroid therapy, which leads to remission in approximately 80 % of cases (steroidsensitive nephrotic syndrome) [2]. However, 80 % of children with steroid-sensitive nephrotic syndrome experience one or more relapses, [3] and 50 % of these children have frequent relapses [4]. Those with frequently relapsing nephrotic syndrome are prone to suffer steroid-induced side effects such as obesity, growth impairment, hypertension, diabetes mellitus, osteoporosis, and adrenal insufficiency. Many cases of steroid-resistant nephrotic syndrome, where steroids are ineffective, progress to renal failure. Pediatric idiopathic nephrotic syndrome is a very important disease in the field of pediatric nephrology. The Scientific Committee in the Japanese Society for Pediatric Nephrology previously published the ‘‘Clinical Practice Guideline for Pediatric Idiopathic Nephrotic Syndrome’’ (2013). This is the English translation from the ‘‘Medical Therapy’’ portion of the guideline.

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.

Drug treatment for bronchopulmonary dysplasia in Japan: questionnaire survey.

Bronchopulmonary dysplasia (BPD) is one of the most common complications in premature infants. Although several different drugs have been developed for BPD, there is a wide variation in the choice of drug used among facilities. The aim of this study was to carry out a survey of the current drugs used to treat BPD in Japan. Questionnaires regarding the current use of drugs for BPD were sent to tertiary neonatal units. The response rate was 80% (77/96). Most units used antenatal steroids and oral diuretics for the prevention and treatment of BPD, respectively. Only 4% used caffeine for prevention, whereas 88% used systemic corticosteroids for treatment. Few units used inhaled anticholinergics and i.v. vitamins for the prevention and treatment of BPD, respectively. It was found that the drugs used to treat BPD vary greatly among institutions. Further research is required to develop evidence‐based clinical guidelines for BPD in premature infants.

Guidelines for the management and investigation of hemolytic uremic syndrome.

The first guidelines for the diagnosis and treatment of HUS following the Shiga toxin producing Escherichia coli (STEC) infection was published by The Japanese Society of Pediatric Nephrology (JSPN) in 2000. Since then, there has been considerable advancement in the understanding and treatment of acute encephalopathy one of the most serious complications in HUS. Furthermore, the etiology, conditions and treatments of atypical HUS have been elucidated. Therefore, a set of comprehensive guidelines for HUS that reflects recent clinical evidence is necessary. The aim of this set of guidelines is to provide a support, tool for daily medical practice and to contribute to the standardization and accessibility of HUS-related medical care, as well as to improve level of safety for HUS patients.