Frequently Relapsing Nephrotic Syndrome Research Articles

Efficacy and acceptability of immunosuppressive agents for pediatric frequently-relapsing and steroid-dependent nephrotic syndrome: A network meta-analysis of randomized controlled trials.

A network meta-analysis was conducted to regard the effects of available immunosuppressive medications in pediatric frequently-relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We reviewed systematically 26 randomized controlled trials (1311 patients) that compared any of the following immunosuppressive agents to placebo/nontreatment (P/NT) or another drug for FRNS/SDNS treatment in children. The main outcomes were efficacy and acceptability. At the 6-month, cyclophosphamide, chlorambucil, levamisole, and rituximab had better efficacy than P/NT (odds ratio [OR]: 0.09, 0.03, 0.28, and 0.07, respectively); cyclophosphamide was significantly more effective than azathioprine and chlorambucil. At 12 months, cyclophosphamide, chlorambucil, cyclosporine, levamisole, and rituximab had better efficacy than P/NT (0.10, 0.03, 0.10, 0.23, and 0.07, respectively); Chlorambucil were found to be more efficacious than levamisole and MMF (0.12 and 0.09, respectively). At 24 months, cyclophosphamide, chlorambucil, and levamisole had better efficacy than P/NT (0.09, 0.04, and 0.03, respectively); cyclophosphamide had better efficacy than cyclosporine and vincristine (0.17 and 0.39, respectively). No significant differences in acceptability were found. Our results suggest that cyclophosphamide may be preferred initially in children with FRSN/SDNS, chlorambucil, and rituximab may be acceptable medications for patients with FRSN/SDNS. Long-term follow-up trials focused on gonadal toxicity and limitation of maximum dosage of cyclophosphamide should been carried out.

Usefulness of mizoribine administration in children with frequently relapsing nephrotic syndrome, and the relationship between pharmacokinetic parameters and efficacy: a multicenter prospective cohort study in China.

Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy. There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS). We investigated the efficacy and safety for treating MZR with FRNS. Furthermore, the relationship between efficacy and serum concentration was investigated. A prospective multicenter observational 12-month study was performedfor evaluating the usefulness of MZR with FRNS. Serum MZR concentration was measured, and the relationships between pharmacokinetic parameters (Cmax, AUC), number of relapses, and urinary protein were evaluated. Eighty-two pediatric patients from four hospitals were treated with MZR and prednisone. MZR treatment significantly reduced the number of relapses and steroid doses. A correlation between pharmacokinetic parameters and relapses was observed, which fits well with the sigmoidal Emax model. Even in the relationship between pharmacokinetic parameters and urinary proteins, it was recognized that there was a threshold in the pharmacokinetic parameters for the therapeutic effect similar to the results obtained with the sigmoidal Emax model. Eleven patients (13.4%) experienced mild adverse events. MZR therapy was effective in reducing the number of relapses and steroid doses. No severe adverse reactions were observed. Therapeutically effective serum concentrations were estimated to be Cmax ≥ about 2μg/mL or AUC ≥ about 10μgh/mL. MZR and steroid treatment were effective and safe for pediatric FRNS.

Long-term observation of Rituximab therapy for children with frequently relapsing nephrotic syndrome

Objective To observe the long-term efficacy and adverse reactions of Rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome (FRNS), and to explore the feasible treatment plan of RTX in children with FRNS. Methods FRNS children with RTX[375 mg/(m2·time), 2-3 times] from Department of Pediatrics, Jinling Hospital, Nanjing Clinical School of Southern Medical University between February 2011 and December 2017 were retrospectively reviewed, and followed up for 12-36 months.Age, gender, number of relapses, dose of steroids and immunosuppressants, adverse reactions and laboratory indicators(peripheral blood CD20+ B lymphocyte count, 24-hour urine protein quantification, etc) were observed. Results Thirty-four patients(23 males and 11 females) with FRNS were included in the present study, and the median age for the first RTX treatment was 6 years (2-12 years). After the first treatment, there was complete remission in 34 patients (100%, 34/34 cases), and 12 patients (35%, 12/34 cases) relapsed during follow-up.The number of relapse after treatment[(0.27±0.45) times]significantly decreased compared with that before treatment[(2.94±1.08) times; t=11.9, P<0.05]. After the second treatment, 3 children relapsed due to and no discomfort was found in the first 6 months; 5 of 23 cases (21.7%, 5/23 cases) relapsed once and 11 were unclear in the following 6 months.There was a difference between the 2 treatment intervals <12 months (12.5%, 2/16 cases) and ≥12 months (55.5%, 10/18 cases). After the third treatment, with an interval of 6 to 15 months, 1 of 15 patients(6.67%) relapsed and the rest were stable.In addition, there was a significant difference in the mean accumulated steroid dose of 20 patients between 6 months before treatment [(2.50±0.87) g ]and 6 months after treatment[(1.30±0.97) g; t=6.05, P=0.001]. Of the 15 patients after RTX treatment for 6-12 months Tacrolimus was reduced from [(1.62±0.77) mg/24 h ] to [(0.62±0.96) mg/24 h; t=6.80, P=0.000]. Two patients after RTX first infusion had chest tightness, palpitations, nausea, vomiting, dizziness, and headache, 3 cases had mild upper respiratory tract infection and 1 case had severe pulmonary infection. Conclusion Long-term follow-up of FRNS children treated with RTX turns out to be safe and effective. Key words: Frequently relapsing nephrotic syndrome; Rituximab; Child; Long-term observation

BEHAVIORAL PROBLEMS IN CHILDREN WITH STEROID-SENSITIVE NEPHROTIC SYNDROME: AN IGNORED ASPECT

Background: Nephrotic syndrome (NS) is a common chronic renal disorder in children. Oral glucocorticoids are required in&nbsp;high doses for prolonged periods adding to various comorbidities including psychosocial issues and behavioral problems.&nbsp;Objectives: This study was done to analyze the behavioral profile of children with steroid-sensitive NS (SSNS), also its association&nbsp;with other factors such as mothers’ education, socioeconomic status, and age distribution. Materials and Methods: This was a&nbsp;questionnaire (child behavior checklist)-based cross-sectional study conducted at a tertiary care center. Children from 6 to 15 years&nbsp;with diagnosis of SSNS for the duration of 1 year or more were included in the study. Cases were divided into two groups: Infrequent&nbsp;and frequent relapsing NS (IFRNS)/steroid-dependent NS (SDNS). Equal number of children in 6–15 years age group attending&nbsp;outpatient clinic was taken as controls. Results: Children with SSNS (n=161) had behavioral problems in significant percentage&nbsp;(39.13%) compared to the control group (8.75%). It was observed more in boys (73.02%) who had more hyperactive, aggressive&nbsp;behavior, and externalizing problems. Internalizing problems (anxious/depressed, withdrawn/depressed, and somatic complaints)&nbsp;were significantly more in the study group (17.39%) as compared to none in the control group. Children with FRNS/SDNS course&nbsp;had more significant problems compared to relapse IFRNS group. Age distribution, socioeconomic status, and mother’s education&nbsp;had no significant effect on its occurrence. Conclusion: Significant behavioral problems are observed in children with SSNS and&nbsp;are related to the type of SSNS.

Study protocol: mycophenolate mofetil as maintenance therapy after rituximab treatment for childhood-onset, complicated, frequently-relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicenter double-blind, randomized, placebo-controlled trial (JSKDC07)

BackgroundIdiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children. Approximately 80–90% of patients with childhood INS have steroid-sensitive nephrotic syndrome (SSNS), and can obtain remission with steroid therapy, while the remainder have steroid-resistant nephrotic syndrome (SRNS). Furthermore, approximately 50% of children with SSNS develop frequently-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS/SDNS are usually treated with immunosuppressive agents such as cyclosporine, cyclophosphamide, or mizoribine in Japan. However, 10–20% of children receiving immunosuppressive agents still show frequent relapse and/or steroid dependence during or after treatment, which is defined as complicated FRNS/SDNS. Furthermore, 30% of SRNS patients who obtain remission after additional treatments such as cyclosporine also turn out to be complicated FRNS/SDNS. For such complicated FRNS/SDNS patients, rituximab (RTX) is currently used; however, recurrence after RTX treatment also remains an open issue. Because long-term use of existing immunosuppressive drugs has limitations, development of a novel treatment for maintenance therapy after RTX is desirable. Mycophenolate mofetil (MMF) is an immunosuppressive drug with fewer side effects than cyclosporine or cyclophosphamide. Importantly, recent studies have reported the efficacy of MMF in children with nephrotic syndrome.MethodsWe conduct a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of MMF after RTX therapy in children with complicated FRNS/SDNS. Patients are allocated to either RTX plus MMF treatment group, or RTX plus placebo treatment group. For the former group, MMF is administered at a dose of 1000–1200 mg/m2/day (maximum 2 g/day) twice daily for 17 months after RTX treatment. The primary endpoint is time-to-treatment failure (development of frequent relapses, steroid dependence or steroid resistance).DiscussionThe results will provide important data on the use of MMF as maintenance therapy after RTX to prevent complicated FRNS/SDNS patients from declining into treatment failure. In future, MMF in conjunction with RTX treatment may permit increased duration of remission in ‘complicated’ FRNS/SDNS cases.Trial registrationThis trial was prospectively registered to UMIN Clinical Trials Registry on June 23, 2014 (UMIN Trial ID: UMIN000014347).

Study protocol: high-dose mizoribine with prednisolone therapy in short-term relapsing steroid-sensitive nephrotic syndrome to prevent frequent relapse (JSKDC05 trial)

BackgroundEighty percent of children with steroid-sensitive nephrotic syndrome (SSNS) relapse within 2 years and 40–50% patients show frequently-relapsing nephrotic syndrome (FRNS). Patients showing a relapse within 6 months after initial remission are at high risk of FRNS. Since frequent prednisolone treatment for FRNS induces severe prednisolone side effects, development of a treatment to prevent patients from shifting to FRNS is desirable. Mizoribine is an immunosuppressive drug with fewer side effects than prednisolone. Recent studies reported the efficacy of high-dose mizoribine in children with FRNS.Methods/designWe conduct a multicenter, open, randomized controlled trial to investigate the efficacy and safety of standard prednisolone plus high-dose mizoribine therapy in children with SSNS showing a relapse within 6 months after an initial remission. Patients are allocated to either standard prednisolone alone treatment group, or standard prednisolone plus high-dose mizoribine group. For the former group, mizoribine is administered at a dose of 10 mg/kg/day once daily and continued for 2 years. The primary endpoint is the duration to frequent relapse.DiscussionThe results provide important data on use of high-dose mizoribine to prevent SSNS patients from shifting to FRNS. Since blood concentrations of mizoribine have not been investigated in detail until now, there is a possibility that mizoribine is underestimated in favor of other immunosuppressive drugs. In future, high-dose mizoribine therapy may lead to prevention of relapse in children at high risk of FRNS, and to decreased total dose of prednisolone.Trial registrationUMIN000005103, (Prospectively registered 1st March 2011).

Mycophenolate mofetil versus cyclosporine A in children with primary refractory nephrotic syndrome

Objective: To compare the efficacy and safety of mycophenolate mofetil versus cyclosporine A in treating children with primary refractory nephrotic syndrome. Methods: Conducted a prospective randomized controlled clinical trial in 62 pediatric patients (including 44 boys and 18 girls), age ranged from 2.1 to 17.0 years; 32 cases presented with frequently relapsing nephrotic syndrome (FRNS) and 30 cases presented with steroid-resistant nephrotic syndrome (SRNS), who were admitted to department of Nephrology, Children's Hospital Affiliated to Capital Institute of Pediatrics from October 2013 to October 2015. The patients received either mycophenolate mofetil (20-30)mg/(kg·d) or cyclosporine A (3-5)mg/(kg·d) randomly, on the basis of prednisone treatment. Follow-up interview was conducted regularly for at least one year. Efficacy rate, relapse rate, time required for induction of remission, relapse-free period and prednisone dosage were compared between the two groups. Results: (1) Renal histologic examination, which was available for 17 patients, revealed minimal change disease in 8 patients, mesangial proliferative glomerulonephritis (MsPGN) in five, membranous nephropathy in two, and focal segmental glomerulosclerosis (FSGS) in two. (2) Comparison of mycophenolate mofetil versus cyclosporine A in children with FRNS: There were 14 patients with FRNS in mycophenolate mofetil group and 18 patients with FRNS in cyclosporine A group respectively. The relapse rate (episodes/year) in cyclosporine A group was lower than that of mycophenolate mofetil group (1.0 (0.0, 1.0) vs. 1.0 (1.0, 3.0), Z=-2.405, P=0.016). The relapse-free period (months) in cyclosporine A group was longer than that of mycophenolate mofetil group (10.0 (5.7, 12.1) vs. 5.0 (1.0, 11.0), Z=-1.984, P=0.047). No significant difference in dosage of prednisone was found between cyclosporine A and mycophenolate mofetil groups when followed up for 1 year. (3) Comparison of mycophenolate mofetil versus cyclosporine A in children with SRNS: The efficacy rate was 6/14 in mycophenolate mofetil group and 13/16 in cyclosporine A group. The complete remission rate was 4/14 in mycophenolate mofetil group and 12/16 in cyclosporine A group (P<0.05). The time (months) required for induction of remission in cyclosporine A group was significantly shorter than that of mycophenolate mofetil group (1.0 (1.0, 2.0) vs. 3.0 (2.5, 4.0), Z=-2.529, P=0.011). No significant differences were found between the two groups with respect to relapse-free period and relapse rate. (4) Except that one patient developed hypertensive encephalopathy in cyclosporine A group, no other serious adverse events were recorded. There were no significant differences between two groups with respect to adverse events. Conclusion: Our results indicated that both mycophenolate mofetil and cyclosporine A were effective in the treatment of children with refractory nephrotic syndrome. Cyclosporine A was superior to mycophenolate mofetil in preventing relapses in patients with FRNS and inducing complete remission in patients with SRNS. Although most patients were able to tolerate mycophenolate mofetil and cyclosporine A, but the toxicity and safety of cyclosporine A should be monitored closely.

Three-monthly bolus vitamin D supplements (1000 vs 400 IU/day) for prevention of bone loss in children with difficult-to-treat nephrotic syndrome: a randomised clinical trial

ABSTRACTBackground: Nephrotic syndrome (NS) in children is one of the most common chronic diseases with a remitting and relapsing course. Glucocorticoids (prednisolone) are considered to be the treatment of choice but are associated with osteoporosis. There are no uniform consensus guidelines regarding the optimum dose of calcium and vitamin D for osteoprotection. Some authorities suggest a daily dose of 1000 IU vitamin D for children for osteoprotection, while others suggest a daily dose of 400 IU.Objectives: To compare the efficacy of three-monthly bolus vitamin D supplementation (1000 vs 400 IU/day) to prevent bone loss in children with difficult-to-treat NS (DTNS).Methods: In this parallel-group, open-label, randomised clinical trial, 60 children aged 1–18 years with DTNS [37 with frequently relapsing NS (FRNS), 13 steroid-dependent NS (SDNS) and 10 steroid-resistant NS (SRNS)] were enrolled and block randomised in a 1:1 allocation ratio to receive 1000 IU/day vitamin D (Group A, n = 30) or 400 IU/day (Group B, n = 30), administered as three-monthly bolus supplemental doses. In Group A, vitamin D (cholecalciferol, Calcirol®sachet) was administered as a stat dose of 90,000 IU every three months (calculated for a period of three months at 1000 IU/day). In Group B, vitamin D (cholecalciferol) was administered as a stat dose of 36,000 IU every three months (calculated for a period of three months at 400 IU/day). The proportionate change in bone mineral content (BMC) was studied by dual energy X-ray absorptiometry (DEXA) scan in both groups after vitamin D supplementation by analysing the values of BMC obtained 12 months apart (baseline vs. after 12 months).Results: Sixty children were randomised to receive vitamin D at a dose of either 1000 IU/day (Group A) or 400 IU/day (Group B). The two groups were comparable in their baseline clinical and laboratory parameters (including BMC and bone mineral density (BMD)). The distribution of the three types of NS (FRNS, SDNS and SRNS) was also comparable in both groups. In Group A, there were 19, 6 and 5 children with FRNS, SDNS and SRNS, respectively, and in Group B there were 18, 7 and 5 children with FRNS, SDNS and SRNS, respectively. The proportionate change in BMC was not significantly different between the two groups (median proportionate change in BMC in Group A 13.36% vs 11.59% in Group B, p = 0.22). Overall, BMC increased in both groups (96.7% in each). Only one (3.3%) patient in each group exhibited bone loss. None of the patients had a urinary calcium:creatinine ratio >0.2 at the end of the study.Conclusion: Three-monthly bolus vitamin D dosing regimens administered either as 1000 or 400 IU/day prevent bone loss in children with DTNS who require long-term steroids. Overall, three-monthly bolus supplemental prophylactic vitamin D, either 1000 or 400 IU/day, would seem to be an effective strategy for preventing bone loss in children with DTNS, as evidenced by the extremely low rates of bone loss (3.3% in each group), and is useful for delivering optimal care to children with DTNS. However, since this study was designed as an equivalence trial and not a superiority trial, further studies are required to demonstrate the superiority of the former regimen over the latter.Abbreviations: BMC, bone mineral content; BMD, bone mineral density; DEXA, dual energy X-ray absorptiometry; DTNS, difficult-to-treat nephrotic syndrome; FRNS, frequently relapsing nephrotic syndrome; IFRNS, infrequently relapsing nephrotic syndrome; iPTH, intact parathyroid hormone; NS, nephrotic syndrome; SDNS, steroid-dependent nephrotic syndrome; SRNS steroid-resistant nephrotic syndrome.

Induction prednisone dosing for childhood nephrotic syndrome: how low should we go?

Historically, children with nephrotic syndrome (NS) across British Columbia (BC), Canada have been cared for without formal standardization of induction prednisone dosing. We hypothesized that local historical practice variation in induction dosing was wide and that children treated with lower doses had worse relapsing outcomes. This retrospective cohort study included 92 NS patients from BC Children's Hospital (1990-2010). We excluded secondary causes of NS, age < 1year at diagnosis, steroid resistance, and incomplete induction due to early relapse. We explored cumulative induction dose and defined dosing quartiles. Relapsing outcomes above and below each quartile threshold were compared including total relapses in 2years, time to first relapse, and proportions developing frequently relapsing NS (FRNS) or starting a steroid-sparing agent (SSA). Cumulative prednisone was widely distributed with approximated median, 1st, and 3rd quartile doses of 2500, 2000, and 3000mg/m2 respectively. Doses ≤ 2000mg/m2 showed significantly higher relapses (4.2 vs 2.7), shorter time to first relapse (61 vs 175days), and higher SSA use (36 vs 14%) compared to higher doses. Doses ≤ 2500mg/m2 also showed significantly more relapses (3.9 vs 2.2), quicker first relapse (79 vs 208days), and higher FRNS (37 vs 17%) and SSA use (28 vs 11%). Relapsing outcomes lacked statistical difference in ≤ 3000 vs > 3000mg/m2 doses. Results strongly justify our development of a standardized, province-wide NS clinical pathway to reduce practice variation and minimize under-treatment. The lowest induction prednisone dosing threshold to minimize future relapsing risks is likely between 2000 and 2500mg/m2. Further prospective studies are warranted.

Mycophenolate mofetil for sustained remission in nephrotic syndrome.

The clinical application of mycophenolate mofetil (MMF) has significantly widened beyond the prophylaxis of acute and chronic rejections in solid organ transplantation. MMF has been recognized as an excellent treatment option in many immunologic glomerulopathies. For children with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) experiencing steroid toxicity, MMF has been recommended as a steroid-sparing drug. Uncontrolled studies in patients with FRNS and SDSN have shown that many patients can achieve sustained remission of proteinuria with MMF monotherapy. Three randomized controlled trials have similarly demonstrated that MMF is beneficial in these patients, but less effective than the calcineurin inhibitors cyclosporin A or tacrolimus. Some, but not all, patients with steroid-resistant nephrotic syndrome (SRNS) may also respond to MMF, usually given in combination with other drugs, with partial or complete remission. There are important limitations to the interpretation and comparability of these studies including study design, sample size, patient selection, clinical endpoints, carry-over effects, and duration of follow-up. In all studies, MMF had relatively few side effects, no nephrotoxicity, or no systemic toxicity. MMF is teratogenic, and contraceptive advice is required in females. There is a poor correlation between MMF dose and mycophenolic acid (MPA) exposure and significant inter- and intra-patient variability in drug pharmacokinetics. A higher estimated MPA-AUC0-12 target range than recommended for pediatric renal transplant recipients is essential to prevent relapses. Therefore, therapy should be guided by drug monitoring to avoid relapses. Further studies are needed to test the efficacy of MMF in inducing remission and, as part of a combination therapy, achieving sustained remission in patients with SRNS.

Calcineurin inhibitors and nephrotoxicity in children.

Calcineurin inhibitors (CNIs) are commonly given to transplant recipients of kidneys and other solid organs and to patients with immune disorders, such as steroid-resistant nephrotic syndrome, steroid-dependent nephrotic syndrome, and frequent relapse nephrotic syndrome. Although CNIs remain the most effective available immunosuppressant agent, there is clinical concern regarding possible long-term nephrotoxicity. This concern is especially significant in children who have a longer life expectancy and greater growth rate. In this review, we analyzed the literatures to identify original articles that examined use of CNIs in children who received organ transplantation and nephropathy to assess the available evidence of their nephrotoxicity. PubMed, Elsevier, and Tompson ISI Web of Knowledge were searched for identifying relevant papers. Clinical research supports the presence of CNI-related nephrotoxicity. However, some researchers have questioned the prevalence and seriousness of chronic CNIs nephrotoxicity, especially because the pathological lesions typically associated with long-term CNI use are nonspecific. Many researchers have focused on early markers of CNI nephrotoxicity, and the methods that may help prevent and manage nephrotoxicity. Future research should focus on investigating early markers of CNI nephrotoxicity and strategies for improved immunosuppressant therapy, and developing alternative treatments. CNI-mediated nephrotoxicity should always be taken seriously in clinic.

Prevalence of Vitamin D3 deficiency among pediatric patients with idiopathic nephrotic syndrome in remission - A cross-sectional observational study from Vadodara, Gujarat

Background: Vitamin D deficiency occurs in nephrotic syndrome (NS) through various mechanisms, resulting in loss of both, Vitamin D binding protein and 25-(OH) D, in the urine leading to the risk of bone disorders. Objectives: The objectives of the study were to detect the prevalence of Vitamin D deficiency in children with idiopathic NS during remission. Methods: This study was conducted from April to November 2016 at the pediatric nephrology clinic at a tertiary care hospital in Vadodara. A total of 34 children were enrolled with idiopathic NS in remission, of which 14 had first attack of NS and ten of Frequently Relapsing Nephrotic Syndrome (FRNS) and Infrequently Relapsing Nephrotic Syndrome each. Vitamin D levels were measured using serum levels of 25-(OH) D by chemiluminescence method. Results: Vitamin D deficiency was observed in 28 of 34 (82%) children; of which, 16 (47%) had severe deficiency and 12 (35.2%) had mild to moderate deficiency. Children with the first attack of NS had a median Vitamin D level of 8.17 ng/ml (interquartile range [IQR] 2.9–28), IFRNS had a median of 6.8 ng/ml (IQR 2.9–33), and FRNS had the lowest median of 5.3 ng/ml (IQR 2.9–16). Although there were differences among all the 3 groups, differences were not statistically significant (Kruskal–Wallis 4.89, p=0.08) which showed decreased levels of Vitamin D. Conclusion: High prevalence of Vitamin D deficiency was observed in all 3 groups of idiopathic NS; the lowest being in FRNS. There was no significant association with lower levels of Vitamin D and relapses in NS. More research is needed to assess Vitamin D deficiency and to ensure the effect of Vitamin D supplementation for children with NS.

Response of calcineurin inhibitors therapy in frequently relapsing and steroid resistent nephrotic syndrome: A single-center experience

Background and Objectives: This observational study was conducted to evaluate and compare the efficacy of calcineurin inhibitors in frequently relapsing nephrotic syndrome (FRNS) and steroid-resistant nephrotic syndrome (SRNS). Subjects and Methods: Each group comprised 15 patients who were studied prospectively. These patients were treated with tacrolimus (Tac) or cyclosporine (CSA) concomitant with prednisone, which was subsequently tapered off and stopped. The primary outcome variable was the number of patients who attained a complete remission (CR) or partial remission (PR). Results: Out of 15 patients with FRNS, 11 were children and 4 were adults. In SRNS, out of total 15 patients 7 were children and 8 were adults. There was male preponderance in FRNS children, whereas in SRNS, gender distribution was almost equal. Hypertension was more common in steroid-resistant group (80%) as compared to FRNS (33%). In FRNS, focal segmental glomerulosclerosis (FSGS), and immunoglobulin M variant of minimal change disease were the most common cause, each accounting for 5 patients, whereas FSGS (8 patients) was the most common etiology in SRNS. In FRNS, out of total 4 patients who were treated with CSA, 2 achieved CR and 2 achieved PR. Mean time to achieve remission was 3.2 months. In FRNS, out of 13 patients who were treated by Tac, 7 patients achieved CR and 6 patients achieved PR. Mean time to achieve remission was 2.1 months. In SRNS, out of 3 patients treated with CSA, 1 achieved PR whereas 2 patients did not respond. Time to achieve remission was 5 months. In SRNS, 11 of 14 patients achieved CR and 2 achieved PR. Mean time to achieve remission was 2.5 months. Among 2 patients resistant to CSA 1 achieved CR with Tac and one did not respond to Tac also. Conclusion: Thus, in FRNS patients, both CSA and Tac are almost equally effective whereas in SRNS patients Tac was more effective than CSA and was also effective in 1 patient resistant to CSA.

Long-term outcome of childhood steroid-sensitive nephrotic syndrome

Background: The long-term outcome of childhood steroid-sensitive nephrotic syndrome (SSNS) needs further evaluation. In this study, In this study, we report the long-term outcome of childhood SSNS at our center. Patients and Methods: This is a retrospective review of cohort of children with SSNS followed by cross-sectional follow-up evaluation. We included all children aged ≥16 years with a history of childhood SSNS. Of 45 children diagnosed with SSNS and contacted for follow-up, only 9 children were available for evaluation of long-term outcome. Demographic, socioeconomic, and disease history data were collected through a questionnaire. All the patients were examined and had their urine and blood samples collected for investigations. The data were analyzed using SPSS. Results: The mean age at onset for the 45 children was 7.3 ± 3.9 years. Follow-up revealed that 65.1% had frequent relapsing or steroid-dependent nephrotic syndrome and 34.9% had infrequent relapses. Of nine patients were included in the follow-up study for a median (range) duration of 11 (5–18) years, 2 of the patients were relapsing at the time of the study and two had one or more relapses during the previous year. Estimated glomerular filtration rate (eGFR) declined in two children and the mean eGFR for the whole group was lower at the time of last follow-up than at baseline (P = 0.032). Conclusion: Children with SSNS need careful long-term monitoring of disease activity and kidney function. A larger prospective study is required.

Mycophenolate Sodium for Children with Frequently Relapsing or Steroid Dependent Nephrotic Syndrome.

In this retrospective study, patients with idiopathic frequently-relapsing nephrotic syndrome (FRNS) (n=27) and steroid dependent nephrotic syndrome (SDNS) (n=13) who received enteric coated mycophenolate sodium (ECMS) for at least 6 months, were included for analysis. Primary outcome was response to ECMS, which was defined as complete if there were no relapses, partial response if there was 1 relapse and no response if there were 2 or more relapses within 6 months of initiation. The mean (SD) dose of ECMS was 985.24 (190.82) mg/m2/day. Thirty patients(75%) had complete response, eight (20%) had partial and two (5%) patients did not respond at 6 months. ECMS seems to be a safe and effective as steroid sparing agent in children with FRNS/SDNS.

Levamisole in Frequently-relapsing and Steroid-dependent Nephrotic Syndrome.

To evaluate the efficacy of levamisole in children with frequently relapsing nephrotic syndrome (FRNS) and steroid dependent nephrotic syndrome (SDNS) when administered on an alternate day ('initial therapy' in all cases) or daily basis ('rescue therapy' in whom alternate day therapy failed). The records of 95 children (age 1-18y) with FRNS (62) and SDNS (33), who were treated at the Pediatric nephrology clinic, and received levamisole therapy (maximum 2 y duration, between 2010-2013) with a follow-up period of minimum 1 y, were included. Alternate day levamisole therapy was efficacious in 73.7% (n=70). The overall efficacy of levamisole therapy was 88.4% (n=84). Levamisole therapy decreased the mean (SD) number of relapses from 4.22 (0.46)/y to 1.35 (0.36)/y (P<0.01); and cumulative median (IQR) prednisolone dosage from 4200 (3200-4300) mg/m2 to 1100 (IQR 500-2900) mg/m2 (P<0.001). On a one-year follow up of the cases in whom levamisole therapy was efficacious during therapy (median 24 mo) (n=84), a frequently relapsing or steroid dependent course continued to persist in 48.8% (41), necessitating oral cyclophosphamide (n= 22) or mycophenolate mofetil (n=19). Daily levamisole therapy was useful in 56% of children who demonstrated failure while on alternate day levamisole therapy, and could be a useful therapeutic option in FRNS and SDNS.

Correlation between Serum Magnesium and Calcium Level in Children with Idiopathic Nephrotic Syndrome during Nephrosis

Background: Biochemical alteration is a common phenomenon in all kidney disease including nephrotic syndrome (NS).Objective: To evaluate the magnesium (Mg) level in patients with nephrotic syndrome and its relation to calcium.Methods: In this observational cross sectional study,we measured serum magnesium and serum calcium levels in children with nephrotic syndrome.It was conducted in the Department of Pediatrics, Dhaka Shishu(children) Hospital, Dhaka, from January 2015 to June 2015. A total of fifty four diagnosed cases of nephrotic syndrome were divided into initial episode, first relapse,infrequent relapse and frequent relapse. Mean level of serum magnesium and calcium of all four groups were then compared.Results :The mean level of serum magnesium during initial episode was 2.28±0.36mg/ dl and it was 2.04±0.29,2.06±0.29 and 1.76±0.32mg/dl during first relapse, infrequent relapse and frequent relapse respectively. The mean serum magnesium level in different patterns of nephrotic syndrome was found to be statistically significant. Hypomagnesemia was mostly found in frequent relapse nephrotic syndrome patients. The mean level of serum calcium during initial episode was 2.01±0.16 and it was 1.98±0.17,2.06±0.13 and 2.05±0.15 during first relapse, infrequent relapse and frequent relapse respectively. The mean serum calcium level in different patterns of nephrotic syndrome was found to be statistically insignificant. There was no significant corelation between calcium level with magnesium level (r = -0.08, p = 0.28).Conclusion: Hypomagnesemia is commonly found in frequent relapse nephrotic syndrome. There was no significant correlation between calcium with magnesium level.Bangladesh J Child Health 2016; VOL 40 (3) :139-143

Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab.

Although rituximab effectively prevents relapses of complicated frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS), data of long-term outcomes and safety are limited. Fifty-one patients (age, 3-38years) with childhood-onset complicated FRNS or SDNS, who received rituximab in investigator-initiated multicenter prospective trials were enrolled. Rituximab was administered at 375mg/m2 once weekly for 4weeks, and immunosuppressive agents were discontinued according to the study protocol. We investigated relapses, re-administration of immunosuppressive agents, additional rituximab treatment, body height, renal function, and late adverse events during the observation period. Forty-eight patients (94%) developed relapses during the observation period (median, 59months) and the 50% relapse-free survival was 261days. Thirty patients (59%) developed SDNS, 44 (86%) required re-administration of immunosuppressive agents, and 22 (43%) received additional rituximab treatment. All patients who were receiving immunosuppressive agents at rituximab treatment required either immunosuppressive agents or additional rituximab treatment. On the contrary, 5 of the 13 patients without immunosuppressive agents at rituximab treatment required neither immunosuppressive agents nor additional rituximab treatment and 3 of them did not develop relapse during observation period. Growth failure due to steroid toxicity did not progress and none of the patients developed chronic renal insufficiency. None of the patients suffered from rituximab-related late adverse events. As most patients suffer from relapses after B-cell recovery, long-term immunosuppressive agents or additional rituximab treatment is necessary. However, some patients who can discontinue immunosuppressive agents before rituximab treatment may achieve long-term remission after rituximab treatment without immunosuppressive agents.

Rituximab for Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome in Adults: A Retrospective, Multicenter Study in Spain.

Patients with difficult-to-treat idiopathic nephrotic syndrome (INS), steroid-dependent nephrotic syndrome (SDNS), or frequently relapsing nephrotic syndrome (FRNS) require long-term immunosuppressive therapy. Rituximab offers an alternative treatment for patients with disease that has not responded to multiple therapies. Our objective was to determine the efficacy and safety of rituximab in adult patients with difficult-to-treat (SDNS or FRNS) INS. We performed a retrospective multicenter study that included 50 adults with difficult-to-treat INS in six Spanish centers. All patients were treated with steroids in combination with another immunosuppressant: 28 patients received rituximab as the additional treatment (rituximab group), and the other 22 patients not treated with rituximab served as the control group. Of the patients treated with rituximab, 23 (82%) experienced complete remission, 20 (71%) had no relapses after receiving rituximab, and 13 (46%) did not receive any immunosuppressant. Of those in the control group, 14 (63%) experienced complete remission, including eight without immunosuppressants (29%). The rituximab group experienced highly significant reductions in total number of relapses per year (p < 0.001), proteinuria (p = 0.03), steroid doses (p = 0.002), and tacrolimus doses (p = 0.001). Mean follow-up after rituximab was 31±26 months (range 8-86). The need for steroids and other immunosuppressants to achieve sustained remission was lower in the rituximab group than in the control group. Rituximab treatment was safe and well tolerated. It effectively reduced the incidence of relapses and need for maintenance immunosuppressive therapy in adults with difficult-to-treat INS.

Nephrotoxicity in children with frequently relapsing nephrotic syndrome receiving long-term cyclosporine treatment.

Steroid-sparing drugs, such as cyclosporine, are recommended as treatment for children with frequently relapsing nephrotic syndrome (FRNS) and steroid-related toxicities. We recently reported a high rate of relapsing nephrotic syndrome 2years after discontinuation of cyclosporine treatment, suggesting that long-term treatment is necessary. Cyclosporine-associated nephrotoxicity (CAN) is a potential side effect of long-term cyclosporine treatment. We retrospectively reviewed pediatric patients with FRNS treated with cyclosporine for ≥3years at a single center between 1999 and 2012. The cyclosporine dose was adjusted to maintain the whole-blood cyclosporine trough level at 80-100ng/ml for 6months, at 60-80ng/ml for 18months, and then at around 50-60ng/ml thereafter. Maintenance dose of prednisolone was not prescribed. CAN was graded in terms of arteriolar hyalinosis and the degree of interstitial fibrosis. Thirty-six children (28 males) were enrolled in the study. The median age at the start of long-term cyclosporine treatment was 9.4years. The median duration of the longest period of cyclosporine treatment was 4.5years. Most CAN cases were characterized by arteriolar hyalinosis. The frequency of CAN was positively correlated with the duration of cyclosporine treatment, with an odds ratio (95% confidence interval) for CAN of 3.84 (0.79-18.74) after 2-5 years and 6.60 (1.18-36.94) after >5years of cyclosporine treatment (vs. 0-2 years). Although the frequency of CAN was correlated with the duration of cyclosporine treatment in our pediatric patient population, most cases of CAN involved arteriolar hyalinosis. We conclude that long-term cyclosporine treatment is useful for treating FRNS in children, providing its dose is controlled and kidney biopsies are regularly performed.