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Background: Although recent studies have shown that more than half of children with steroid-dependent nephrotic syndrome (SDNS) may continue to have active disease beyond childhood, the long-term outcome in this cohort treated with mycophenolate mofetil (MMF) after cyclosporine remains unknown, particularly in adulthood., Methods: We conducted a retrospective study of 44 adult patients (median age, 22.3 years) who received MMF for complicated SDNS (median age at MMF initiation, 13.3 years) at a single center. Complicated SDNS was defined as the case continuing to relapse after cyclosporine (CsA) treatment. When patients experienced relapses despite MMF initiation, they additionally received a rituximab infusion. The primary endpoint was the probability of achieving treatment-free remission for > 2 years., Results: Prior to MMF initiation, all patients received CsA for a median of 46 months and 19 received the 12-week cyclophosphamide. After switching from CsA to MMF, only four patients did not relapse during a median follow-up period of 9.6 years. At the last visit, only 15 of the 44 patients achieved treatment-free sustained remission. Multivariate analysis revealed that young age (< 6 years) at onset of nephrotic syndrome (odds ratio, 11.3) and the experience of steroid dependency during initial CsA treatment (odds ratio, 29.8) were the independent risk factors of active disease into adulthood after MMF initiation., Conclusions: Although none developed renal insufficiency and severe adverse effects of therapy, the introduction of MMF after CsA treatment may not be necessarily associated with improved long-term outcome of children with complicated SDNS.

Background: Recent randomized studies indicate that mycophenolate mofetil (MMF) is inferior to cyclosporine (CsA) in preventing relapses of nephrotic syndrome (NS). During the last decade, rituximab (RTX) has emerged as a rescue therapy in patients with complicated, frequently relapsing, or steroid-dependent NS., Case-Diagnosis/treatment: After introducing RTX in our single center, we analyzed 26 patients with steroid-dependent NS who had relapses while receiving long-term CsA and who were subsequently switched to MMF. MMF was adjusted to maintain a targeted predose mycophenolic acid (MPA) level of 2-5 μg/ml. Moreover, for patients who required MMF and high-dose prednisolone (PSL) to maintain remission, a single infusion of RTX (375 mg/m(2)) was added. The primary endpoint was the probability of achieving PSL-free remission for >1 year. At a mean follow-up of 28.8 ± 9.9 months, 11 of 26 patients (42 %) required RTX treatment, and 22 of those patients (85 %) achieved PSL-free sustained remission. The mean predose MPA levels for patients who achieved PSL-free sustained remission were significantly higher compared with those for patients who did not (3.1 μg/ml vs. 1.7 μg/ml, p < 0.05)., Conclusions: After RTX introduction, most patients were able to switch from CsA to MMF and achieve sustained PSL-free remission.

Background: Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats., Methods: Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated., Results: Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsA nephrotoxicity., Conclusion: These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity.

Unlabelled: The efficacy of rituximab (RTX) as the sole therapy for preventing relapses of nephrotic syndrome (NS) is transient in most patients; therefore, the optimal therapy required for maintaining a successful response to a biological agent remains a challenge. We conducted a prospective study to compare the efficacy of cyclosporine (CsA) with that of mycophenolate mofetil (MMF) as maintenance therapy after a single infusion of RTX. Of 29 patients with persistent steroid-dependent NS despite the use of CsA and/or MMF, 13 without chronic nephrotoxicity continued CsA therapy, maintaining a 2-h post-dose CsA level of 400-500 ng/ml (CsA group). The remaining 16 were treated with MMF, maintaining a pre-dose level of 2-5 μg/ml of mycophenolic acid (MMF group). The median duration of CsA and MMF treatment was 18 and 19 months, respectively. Despite the mean number of relapses before RTX treatment being significantly lower in the MMF group than in the CsA group (2.3/year vs. 4.6/year, p < 0.01), treatment failure occurred more frequently in the MMF group (7/16) than in the CsA group (2/13). The rate of sustained remission was also significantly higher in the CsA group than in the MMF group (p < 0.05)., Conclusion: In patients with severe steroid-dependent NS, CsA appears to be more effective than MMF for maintaining remission after a single infusion of RTX.

Background: Although once-daily cyclosporine (CsA) therapy may have greater nephrotoxic-sparing effects than standard twice-daily therapy, little information is available in children with steroid-dependent minimal change nephrotic syndrome (MCNS) regarding histological analysis after long-term once-daily administration., Case-Diagnosis/treatment: A prospective study of the clinical efficacy and comparison between pre- and post-treatment renal biopsy findings in ten children (mean age, 8.8 years) with steroid-dependent MCNS who were administered once-daily CsA therapy for more than 24 months (mean ± SD, 30 ± 3.7) was performed in Saitama Children's Medical Center. Administration of once-daily CsA therapy (mean dose, 2.8 ± 0.6 mg/kg/day; mean C2 levels, 670 ± 64 ng/ml) resulted in a significant reduction in the median relapse rate from 4.6 to 0.2 times per year, and five patients did not experience a relapse of NS. Furthermore, mean threshold of prednisolone dose significantly reduced from 1.2 to 0.02 mg/kg on alternate days. However, two patients showed evidence of chronic CsA nephrotoxicity (CsAN)., Conclusions: Once-daily CsA therapy appears to be effective in children with steroid-dependent MCNS. However, follow-up renal biopsies should be performed to investigate the presence of CsAN after more than 24 months of treatment with once-daily regimen as well as with the conventional twice-daily regimen.

Although cyclosporine (CsA) therapy is effective in the management of children with steroid-dependent nephrotic syndrome (SDNS), a recent study has revealed that the use of CsA itself was a significant predictor of NS relapse in adulthood. The efficacy of single daily high-dose mizoribine (MZR) therapy was assessed in 10 children with SDNS (mean age, 6.2 years) who had never been treated with CsA previously. MZR was started at 5 mg/kg, administered as a single daily dose after breakfast, and the dose was adjusted to achieve 2-h post-dose MZR levels (C2) of approximately 3 μg/ml. In 9 of the 10 patients, treatment with a single daily dose of MZR (mean dose, 8.4 mg/kg/day) over a period of 22 months (median) resulted in significant reduction of the mean prednisolone dose from 0.39 to 0.15 mg/kg/day and the median 12-month relapse rate from 3.0 to 0.4 episodes/12 months. Although cyclophosphamide was initiated in one patient because of treatment failure, none of the 10 patients required treatment with CsA during the observation period (median, 33 months). These data indicate that single daily high-dose MZR therapy is possibly useful in treating children with SDNS and that it may also eliminate the need for CsA in some patients.

Background: Cyclosporine A (CsA) is an effective agent for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can also be complicated by renal toxicity. Because no biochemical markers from urine or blood samples have yet been established for detecting CsA-induced renal injury to date, repeated renal biopsies are therefore required for all patients with long-term CsA treatment. The purpose of the present study was therefore to detect early change of CsA nephropathy (CsAN) using blood samples., Methods: Several biochemical markers were analyzed in an attempt to examine the renal function in 24 patients with FR-SDNS who had been treated with CsA. Those included serum cystatin C and indoxyl sulfate, as well as creatinine and beta2-microglobulin., Results: Renal biopsy findings indicated chronic CsAN in 13 of the 24 patients. Among those markers, only serum indoxyl sulfate was significantly elevated in patients with CsAN., Conclusions: It may be possible for measurement of serum indoxyl sulfate level to replace repeated renal biopsies in evaluation of chronic CsAN in pediatric patients with FR-SDNS.

Rituximab (RTX) has been successfully used as a rescue therapy in children with steroid-dependent nephrotic syndrome (SDNS). However, little is known regarding maintenance therapy after a successful response to RTX in such patients. The efficacy and safety of a single RTX infusion (375 mg/m(2)) were assessed in ten patients who had persistent SDNS associated with minimal-change disease (MCD) despite the long-term use of cyclosporine (CsA). The mean follow-up after RTX infusion was 17 months. Applying RTX resulted in a significant reduction in the mean prednisolone (PSL) dose from 0.39 +/-0.18 to 0.15 +/- 0.14 mg/kg per day. The mean 12-month relapse rates significantly decreased from 4.1 +/- 1.7 to 0.6 +/- 0.6. All but one patient who had continued CsA as maintenance therapy after a single RTX infusion were able to withdraw from PSL without any relapses during the study period, whereas the remaining five patients who discontinued CsA experienced relapses after CD19 cells re-emerged, leading to the reintroduction of CsA or an additional RTX infusion. Infusion reactions occurred in five of ten patients. These data indicate that a single RTX infusion may improve response to CsA in patients with persistent SDNS due to the phenomenon of secondary resistance to CsA.

We retrospectively analyzed the long-term outcome of 82 children (SRNS group, 10; SDNS group, 35; IRNS group, 37) who were initially treated with the ISKDC regimen at the Saitama Children's Medical Center. The ISKDC regimen consisted of PSL 60 mg/m2/day for 4 weeks, followed by 40 mg/m2 on alternate days for another 4 weeks. The aims of our study were to identify factors at onset that could predict the relapse pattern after using the initial ISKDC regimen, and to assess the prognosis and renal histology after long-term CsA therapy in 31 children. All of six asymptomatic children without edema and identified by chance proteinuria on a urinary screening program had an extremely favorable clinical course. Initial remission time of 9 or more days and the time interval from the initial therapy to the first relapse were significant predictors of steroid dependency. The sensitivity and specificity of these findings were 100% and 90%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In addition, after the introduction of CsA therapy, termination of steroid therapy was achieved in 56% of patients with SRNS, and 64% of SDNS, respectively. However, after CsA therapy was tapered or stopped, most patients (21/20: 95%) developed relapses of NS. Of these, 76% (16/21) returned to SDNS, resulting in the reintroduction of CsA. Ten of 22 patients taking CsA (mean duration 31.3 months) had chronic nephrotoxicity. In conclusion, the initial ISKDC regimen is useful for the early prediction of whether or not the patient will develop SDNS. When pediatric nephrologists introduce CsA therapy in children with SDNS, an alternative strategy after long-term use of the agent should be considered.

The therapeutic benefits of Cyclosporine A (CsA) are often limited by the chronic nephrotoxicity of its long-term use. Chronic nephrotoxicity is manifested by renal function impairment and progressive histopathological kidney lesions characterized by tubular vacuolization, tubular necrosis, interstitial fibrosis, and afferent arteriolopathy. This study tested the hypothesis that the concurrent administration of Mizoribine (MZR) may improve chronic CsA nephrotoxicity. Sprague-Dawley male rats were divided into the following four groups: group 1, control (n = 6); group 2, treated with CsA alone (n = 5); group 3, treated with CsA and MZR (n = 4); and group 4, treated with MZR alone (n = 6). The anti-inflammatory and antifibrotic effects of MZR were studied by evaluating the concentrations of the inflammatory mediator, osteopontin, renal function, and histopathology. The interstitial fibrosis was stained blue with Elastica-Massontrichrome and the sections were quantified. The CsA-treated rats showed decreased renal function and increased histologic parameters in comparison with the control rats and also showed significantly increased interstitial fibrosis area and macrophage in comparison with the control rats. The CsA MZR treatment significantly improved the interstitial fibrosis area and macrophage in comparison with the CsA-treated rats. On the basis of these findings, we suggest MZR effectively attenuates renal macrophage accumulation and the progression of interstitial fibrosis.

Background: Mycophenolate mofetil (MMF) is being used increasingly in children with steroid-dependent nephrotic syndrome (SDNS). However, there is limited information on the optimal therapeutic range for mycophenolic acid (MPA), the active metabolite of MMF, in these patients., Methods: 26 patients with SDNS (mean age 13.1 years, 19 with minimal change disease and 7 with focal segmental glomerulosclerosis) who had received MMF for at least 6 months after longterm cyclosporine (CsA, mean 56 months) at Saitama Children's Medical Center between September 2002 and August 2008 were analyzed. MMF was introduced at an initial dose of 250 mg/12 h, adjusted to maintain target predose MPA at greater than 2 microg/ml (maximum 1 g twice daily) gradually over 4 weeks. After the introduction of MMF, the dosages of both CsA and prednisolone (PSL) were tapered off if possible., Results: The mean MMF dose required was 34 +/- 6 mg/kg, which maintained the mean predose MPA levels of 3.1 mg/ml. In 26 patients, treatment with MMF for a mean follow-up period of 19 months (range 7 - 42), resulted in a reduction of the mean PSL dose from 0.33 +/- 0.23 to 0.17 +/- 0.11 mg/kg per day (p < 0.01) and mean CsA dose from 3.2 +/- 1.7 to 1.3 +/- 1.8 mg/kg per day (p < 0.01). The mean 12-monthly relapse rates decreased from 2.5 +/- 1.4 to 0.8 +/- 1.2 episodes (p < 0.01). In 20 patients treated with MMF (77%), the dose of PSL and/or CsA was successfully tapered with a reduction in the relapse rates. In 6 patients, however, CsA therapy was reintroduced or its dose was increased because of treatment failure. The patients whose average predose MPA levels were less than 3 microg/ml were significantly likely to have treatment failure (p < 0.05). 2 patients reduced the MMF dosage because of anemia or herpes labialis. However, no severe gastrointestinal discomfort was seen in any patients. Despite long-term CsA therapy, marked tubulointerstitial fibrosis developed during MMF therapy in surveillance biopsies of only one of these five patients., Conclusions: Therapy with MMF based on the predose MPA levels can be a less toxic alternative to CsA or in some cases a useful additional medication to allow for a reduction in the CsA and/or PSL dosage.

Background: A recent study on renal transplant patients has shown that a single dose of cyclosporine (CsA) has added the advantage of decreasing dosages and adverse effects, while maintaining graft function. However, the efficacy of this regimen in children with idiopathic frequent-relapsing nephrotic syndrome (NS) remains controversial., Methods: 20 children with steroid-dependent NS or CsA-dependent NS (18 with minimal change disease, MCD and 2 with focal segmental glomerulosclerosis, FSGS) were enrolled in this prospective study. CsA was commenced at 1.5 â 2 mg/kg, given as a single daily dose before breakfast, and the dose was adjusted to reach 2 hours post-dose CsA levels (C2) of 600 - 800 ng/ml., Results: In 9 out of 18 patients with MCD, treatment with single-daily CsA for a median of 13 months (range 7 - 21) resulted in a reduction of mean minimum prednisolone (PSL) dose from 1.1 A+/- 0.55 to 0.04 A+/- 0.09 mg/kg on alternate days (p < 0.01), and the median relapse rate from 1.3 (1.1 - 2.5) to 0 (0 - 0.2) episodes/6 months (p < 0.01). Of them, PSL could be weaned off in 7 patients (4 of 6 with steroid-dependent NS, only 3 of 14 with CsA-dependent NS) without relapse of NS while on this therapy. However, 11 out of 20 were considered to have treatment failure: 1 with steroid-dependent NS and 10 with CsA-dependent NS. In 2 patients having FSGS, this method showed no beneficial effects. In 18 patients with MCD, relapse free ratio on single-daily CsA therapy was significantly higher in patients whose average C2 levels were greater than 700 ng/ml (p < 0.05)., Conclusions: Our experience demonstrates that single-daily low-dose CsA therapy maintaining C2 levels greater than 700 ng/ml may be effective in children with steroid-dependent NS or MCD, with no relapse. In contrast, the usefulness of this regimen in children with CsA-dependent NS appears to be limited.

Cyclosporine A (CsA) has relieved children with steroid-dependent nephrotic syndrome (NS) from steroid toxicity. However, most patients frequently relapse again when CsA is withdrawn, resulting in the development of CsA nephropathy for its long-term use. In order to assess the efficacy of mycophenolate mofetil (MMF) therapy, we prospectively analyzed 12 children with idiopathic steroid-dependent NS requiring long-term CsA therapy with MMF for at least 6 months. Mean follow-up after starting MMF was 11 months (range 6-42). The mean MMF dose required was 610+/-95 mg/m(2)/12 h, which maintained mean predose mycophenolic acid (C0-MPA) levels of 2.4+/-1.1 mcg/ml. Treatment with MMF resulted in CsA and/or prednisolone (PSL) sparing, with a reduction in mean CsA dose from 3.5+/-1.3 to 1.5+/-2.4 mg/kg/day (p<0.01), and mean PSL dose from 0.29+/-0.16 to 0.21+/-0.11 mg/kg/day (p<0.05). Nine of 12 patients (75%) were finally able to be weaned off CsA. Mean relapse rates decreased from 2.7+/-1.6 to 0.6+/-0.9 episodes/year (p<0.01). Relapse-free ratio on MMF therapy was lower in patients whose average C0-MPA levels were less than 2 mcg/ml (p<0.05). Our experience demonstrates that MMF therapy results in significant CsA and/or steroid sparing and reduction in relapse rates in children with CsA-dependent NS.

Background: Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients., Aims and Methods: In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50-150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed., Results: Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6-144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN., Conclusion: An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.

Cyclosporin A (CsA) is an effective treatment for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can be complicated by renal toxicity and a high incidence of relapses after withdrawal. We report 9 adolescent patients with childhood-onset FR-SDNS who had been treated with long-term CsA that resulted in moderate-to-severe CsA nephropathy (CsAN). They were treated with high-dose (mean: 10.1 mg/kg per day) mizoribine (MZR) in an attempt to allow weaning of CsA and/or steroid therapy, and reduce the frequency of relapses. Seven out of 9 patients were weaned off CsA by 1-year follow-up, although in the remaining 2 patients, MZR did not show any beneficial effects. Overall, this high-dose MZR therapy results in significant steroid sparing and reduction in relapse rates in our patients. Our experience shows that high-dose MZR therapy in patients with FR-SDNS who are also CsA-dependent appears to be effective in reducing CsA exposure as well as in decreasing the frequency of relapses.