Relapsing Steroid-sensitive Nephrotic Syndrome Research Articles

Short Course of Daily Prednisolone During Upper Respiratory Tract Infection for Children With Relapsing Steroid Sensitive Nephrotic Syndrome

PREDNOS 2 was a double blind placebo controlled trial done to investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection—related relapses. It evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. At the beginning of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. The primary outcome was the incidence of first upper respi-ratory tract infection-related relapse. The modified intention-to-treat analysis population comprised 271 children (mean (SD) age, 7.6 (3.5) years; 64.2% male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) in the predniso-lone arm and 58 (44.3%) in the placebo arm (adjusted risk difference, 0.02; 95% CI, 0.14 to 0.10; P =0.70). No evidence was found that the treatment effect differed according to background immuno-suppressive treatment. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40–1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81–1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P=0.09). The authors concluded that, results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK and further work is needed to study the inter-ethnic differences in the study response.

FC 132SHORT COURSE DAILY LOW-DOSE PREDNISOLONE AT THE TIME OF UPPER RESPIRATORY TRACT INFECTION (URTI) IN NON-SELECTED CHILDREN WITH RELAPSING STEROID SENSITIVE NEPHROTIC SYNDROME DOES NOT PREVENT URTI-RELATED RELAPSE: THE PREDNOS 2 TRIAL

Abstract Background and Aims At least 80% of children with steroid sensitive nephrotic syndrome (SSNS) have relapses and many are triggered by upper respiratory tract infections (URTIs). Previous small studies (4 studies, 232 patients in total), mostly in children already taking maintenance corticosteroid in countries where URTI epidemiology is different to Europe, showed that giving daily low-dose prednisolone for 5-7 days during an URTI reduces the risk of relapse. The objective of the PREDNOS 2 trial was to determine if these findings were replicated in a large UK population of children with relapsing SSNS on different background medication or none. Method A randomised, double-blind, placebo-controlled trial, including a model-based economic evaluation was carried out in 122 UK paediatric departments. Between February 2013 and January 2019, 365 children with relapsing SSNS (mean age: 7.6 ± 3.5 y) were recruited from 91 sites and randomised (1:1) according to a minimisation algorithm based on background treatment (no background treatment; low-dose prednisolone only; low-dose prednisolone and other immunosuppression; other immunosuppression only). At the start of an URTI, children received 6 days of prednisolone 15 mg/m2 or matching preparation of placebo. Those already taking alternate day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 or their alternate-day dose, whichever was the greater. The primary outcome was the incidence of first URTI-related relapse (URR) following any URTI over 12 months. Secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention to treat. The economic evaluation used trial data and a decision-analytic model to estimate Quality-Adjusted-Life-Years (QALYs) and costs at 1-year, which were then extrapolated over 16 years. Results 80 children completed 12 m follow-up without an URTI. Consent was withdrawn for 32 children, 14 prior to an URTI, leaving a modified intention to treat analysis population of 271 children (134 and 137 in prednisolone and placebo arms respectively). There were 384 URTIs and 82 URRs in the prednisolone arm, and 407 URTIs and 82 URRs in the placebo arm. The number of patients experiencing a URR was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms respectively (adjusted risk difference: -0.024, 95% CI: -0.14 to 0.095; P=0.7). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. A post-hoc subgroup analysis assessing primary outcome in 58 children of South Asian ethnicity (RR 0.66, 95% CI: 0.396 to 1.105) versus 213 of other ethnicity (RR 1.11, 95% CI: 0.806 to 1.535) showed possible efficacy of intervention in those of South Asian ethnicity (test for interaction P=0.09). Giving daily prednisolone at the time of an URTI was found to increase QALYs and decrease overall costs, when compared to standard care, a finding that was robust to sensitivity analysis. Conclusion In a large and methodologically-robust study, PREDNOS 2 has shown that giving 6 days of daily low-dose prednisolone at the time of an URTI does not reduce the risk of relapse of nephrotic syndrome in UK children, but could offer a cost-effective use of health care resources. Further work is needed to investigate inter-ethnic differences in treatment response, and the pathogenesis of individual viral infections and their effect on nephrotic syndrome.

Low-dose versus conventional-dose prednisolone for nephrotic syndrome relapses: a randomized controlled non-inferiority trial.

Reduction of steroid exposure in relapses of steroid-sensitive nephrotic syndrome (SSNS) is under-researched. In this randomized controlled non-inferiority trial, 1-12-year-old children with relapse of SSNS were randomized to receive prednisolone 1 mg/kg/day (low dose) or 2 mg/kg/day (standard dose) until disease remission or day 15, whichever was earlier. Therapy was switched to 2 mg/kg/day in children in low-dose group not in remission by day 15. Primary outcome was days to remission, and secondary outcome being pattern of subsequent relapse(s) over 1 year. Estimating time to remission of 8 ± 2.5 days with standard-dose therapy, non-inferiority margin of 2 days, 90% power, and α-0.05, 60 patients were randomized. Of the 60 children (30 in each group) enrolled, 4 (one in low-dose group) failed remission by day 15. Time to remission was comparable between low-dose and standard-dose groups [9.0 ± 2.2 vs. 8.6 ± 2.2 days; mean difference (95% CI) 0.4 (- 0.79 to 1.59) days; p = 0.49], thus establishing non-inferiority of low dose. Median time to subsequent relapse was 86 (IQR 74.8, 97.2) and 150 (IQR 59.0, 240.9) days, in low- versus standard-dose groups, respectively (log rank p = 0.39). In follow-up, proportion of children having relapses, frequency of relapses, proportion with frequent relapse/steroid dependent (FR/SD), and cumulative corticosteroid dose taken were comparable between groups. This study shows that time to achieve remission after treatment of a relapse with low-dose prednisolone is non-inferior to that after treatment with conventional dose in children with SSNS. The proportion of children achieving remission, further course, and pattern of relapses was comparable between both groups.

Decreased Circulating Transitional B-Cell to Memory B-Cell Ratio Is a Risk Factor for Relapse in Children with Steroid-Sensitive Nephrotic Syndrome

Introduction: A significant proportion of children with SSNS (steroid-sensitive nephrotic syndrome) experience recurrence. Reliable biomarkers to predict flare are currently lacking because the pathogenesis of SSNS remains obscure. Objective: Since B cells may be involved in the pathogenesis of SSNS, we aimed to identify perturbations of B-cell subsets that might predict SSNS relapse. Methods: We measured levels of circulating B-cell subsets in 69 SSNS children by flow cytometry, between 2018 and 2019. We divided them into a relapse group and a nonrelapse group according to whether a relapse occurred within 1 year of follow-up. We used Cox survival analysis to assess correlations between B-cell subsets and relapse. In addition, recurrence-free survival curves were calculated using the Kaplan-Meier method. Results: The proportion of transitional B cells was significantly lower in the relapse group (5.3 ± 5.1% vs. 8.7 ± 4.3% in nonrelapse group, p = 0.007), while the proportion of memory B cells was significantly higher (8.4 ± 3.0% vs. 5.8 ± 3.3% in nonrelapse, p = 0.002). There was a significant decrease in the transitional B-cell to memory B-cell ratio (T/M) in the relapse group (p < 0.001). Univariate analysis revealed that transitional B cells, memory B cells, and the T/M ratio were significantly correlated with relapse in SSNS patients (p < 0.05). Multivariate analysis revealed that only T/M ratio (hazard ratio 0.278, 95% confidence interval 0.085–0.908, p = 0.034) was an independent risk factor for recurrence-free survival in SSNS patients. A cutoff value for the T/M ratio of 1.16 resulted in a sensitivity of 90% and specificity of 80% (area under the curve 0.909; p < 0.001). Kaplan-Meier curves of cumulative relapse-free survival, stratified by this cutoff value, were constructed, which showed that the cumulative relapse-free rates for cutoff values of >1.16 (n = 38) and ≤1.16 (n = 31) were 76.3 and 29.0%, respectively (χ² = 18.416, p < 0.001). Conclusions: Decreased transitional B/memory B ratio is associated with SSNS recurrence in the reported cohort. Thus, it may prove to be a useful marker to predict SSNS relapse in children.

Results of the PROPINE randomized controlled study suggest tapering of prednisone treatment for relapses of steroid sensitive nephrotic syndrome is not necessary in children

Corticosteroid-related toxicity in children with steroid-sensitive nephrotic syndrome is primarily related to the cumulative dose of prednisone. To optimize treatment of relapses, we conducted the PROPINE study, a multicentric, open-label, randomized, superiority trial. Seventy-eight relapsing children aged 3-17 years who had not received steroid-sparing medications during the previous 12 months were randomized to receive, from day five after remission, either 18 doses of 40 mg/m2 of prednisone on alternate days (short arm), or the same cumulative dose tapered over double the time (long arm). Patients were monitored with an ad-hoc smartphone application, allowing daily reporting. The primary outcome was the six-month relapse rate at which time, 23/40 and 16/38 patients had relapsed in the long and short arms, respectively (no significant difference). Additionally, 40/78 patients were also enrolled in a secondary crossover study and were allocated to the opposite arm. Altogether, at six months, the relapse rate was 32/40 and 28/40 in the long and short arms, respectively (no significant difference). A post-hoc analysis excluding 30 patients treated with low-dose prednisone maintenance therapy failed to show significant differences between the two arms. No differences in adverse events, blood pressure and weight gain were observed. Thus, our data do not support the prescription of prolonged tapering schedules for relapses of steroid-sensitive nephrotic syndrome in children.

Corticosteroid therapy for nephrotic syndrome in children.

Corticosteroid therapy for nephrotic syndrome in children.

P0401RITUXIMAB VESUS CYCLOPHOSPHAMIDE AS FIRST STEROID SPARING AGENT IN CHILDHOOD FREQUENTLY RELAPSING OR STEROID DEPENDENT NEPHROTIC SYNDROME

Abstract Background and Aims Approximately 50% of children with steroid sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications Method A prospective open label randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia or active infection. The recruited children were allocated either to the oral cyclophosphamide (3mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m2/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months Results 46 subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR: 0.36; 95% CI: 0.09 – 1.45; p=0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (N=10) and 6.3 months in the rituximab group (N=3). Both treatments were associated with a significant (p=?) reduction in prescribed dose of oral alternate days steroid from 1.02 to 0.36mg/kg (Cyclophoshamide) and 0.86 to 0.08mg/kg (Rituximab). Importantly, a significantly (P = 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity beside severe leucopenia and neutropenia on the 7th week of treatment although she showed complete recovery with withdrawal of cyclophosphamide and maintained remission. A minor infusion related reaction was observed in 1 patient (5%) in the rituximab group. Conclusion Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide

Physical development and idiopathic nephrotic syndrome in children

INTRODUCTION.Study of physical development (PD) of children with idiopathic nephrotic syndrome (INS) includes mainly assessment of body height and weight during corticosteroid (CS) therapy; specifics of these criteria before and after the treatment are not sufficiently studied. THE AIM: to study PD of children with INS debut during CS therapy and upon its completion.PATIENTS AND METHODS.A retrospective analysis of PD was performed in 89 patients with INS in Voronezh Regional Children's Clinical Hospital No.1 during 1998-2014 using method of Z-score of body height and weight in comparison with regional standards.RESULTS.At the INS debut body height of 38.2% of the children and body weight of 41.2% accordingly were less than those of healthy children, p&lt;0.001. Children with steroid-sensitive nephrotic syndrome (SSNS) had no difference in body height Z-score during CS therapy (0.17±1.06) and upon its completion (0.28±1.22), p=0.794. Body height was less in steroiddependent patients (SDNS) compared to SSNS patients. Z-score body weight values in children with SSNS were higher during maximum doses of CS (0.94±1.59) and returned to previous values after the therapy (-0.24±1.33), р=0,040. Patients with a frequent relapsing SSNS and SDNS had overweight and obesity remained after prednisone treatment (p=0.009).CONCLUSION.Physical development of children with INS has differences associated with CS therapy. Since body height and weight of children with INS were different from the norms before CS therapy, this could be influenced by genetic factors, which to be studied further. The results can be used to prognose CS therapy influence on PD of patients and assess prognosis of INS.

Increased ischemia-modified albumin levels in children with steroid-sensitive nephrotic syndrome.

Objective:Growing evidence shows that oxidative stress plays an important role in the development and progression of nephrotic syndrome (NS). In this study, we aimed to examine serum IMA levels as an indicator of oxidative stress in children with steroid-sensitive NS (SSNS) in remission and relapse.Methods:This cross-sectional study was carried out at the Pediatric Nephrology Unit of Sanliurfa Training and Research Hospital, Sanliurfa, Turkey, from April 2019 to December 2019. In this study Serum IMA and albumin levels were determined in 70 children with SSNS and 45 healthy controls. Among the children with SSNS, 50 were in remission and 20 were in relapse. Then, adjusted IMA levels were calculated from the IMA/albumin ratio.Results:IMA and adjusted IMA levels significantly increased and albumin significantly decreased in children with SSNS in relapse and remission compared with those of the healthy controls. Moreover, these alterations were more prominent in the relapse group than in the remission group. IMA was inversely correlated with albumin in children with SSNS (r= −0.881, p= <0.001).Conclusions:Our findings demonstrated that elevated IMA and adjusted IMA levels observed in patients with SSNS were associated with increased oxidative stress and could indirectly reflect the degree of oxidative damage in glomerular structures.

Lower prednisone dosing for steroid-sensitive nephrotic syndrome relapse: a prospective randomized pilot study.

Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with prednisone 2mg/kg/day or 60mg/m2/day. Retrospective data support the use of lower doses. We designed a prospective randomized pilot study to investigate the efficacy of different doses in achieving remission of steroid sensitive nephrotic syndrome relapse. The cohort included 30 children with relapsed steroid sensitive nephrotic syndrome, mean age 6.3 ± 3years and mean disease duration 2.2 ± 1.8years. The children were randomized to receive 2, 1.5, or 1mg/kg/day prednisone. The corresponding times to response, defined as the first of 3 consecutive days without proteinuria, were 7.2 ± 1.4, 10.2 ± 5.1, and 9 ± 3.3days; the difference between the 1.5 and 2mg/kg/day groups was statistically significant. One patient each in the 1mg/kg/day and the 1.5mg/kg/day groups failed to respond and were switched to 2mg/kg/day, leading to a response after 3 and 10days, respectively. Mean cumulative prednisone doses in the 3 groups were 45.5 ± 3.4, 42.7 ± 25.9, and 24.9 ± 7.4mg/kg, respectively (P < 0.05).Conclusion: In the present study, treatment of childhood steroid sensitive nephrotic syndrome relapse with prednisone 1-1.5mg/kg/day led to a significantly lower cumulative dose than the standard dose. Treatment with a lower dose may be equally safe and effective to the standard dose.What is Known:• Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with standard-dose steroids.• Treatment with corticosteroids may have significant adverse effects mainly with long-term use.What is New:• Treatment of steroid sensitive nephrotic syndrome relapse with 1-1.5mg/kg/day prednisone may lead to a significantly lower cumulative dose.• Treatment with a lower steroid dose may be as effective as the standard dose in achieving remission of steroid sensitive nephrotic syndrome relapse.

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).

Histopathological Spectrum and Short-Term Outcome of Treatment with Cyclophosphamide in Relapsing Steroid-Sensitive Nephrotic Syndrome.

To determine the short-term outcome of cyclophosphamide (CPO) course in children with relapsing steroid sensitive nephrotic syndrome (SSNS) with different histopathological lesions. Descriptive, observational study. Pediatric Nephrology Department, Sindh Institute of Urology and Transplantation, Karachi, from January 2012 to December 2014. All children with relapsing steroid-sensitive nephrotic syndrome, who underwent renal biopsy and received cyclophosphamide therapy, were included and followed up for 2 years. Histopathological features in renal biopsy, duration of treatment, duration of complete remission and complication frequency was noted. Of the total 74 patients, 47 (63.5%) were males and 27 (36.5%) females. Median age with Interquartile range (IQR) at presentation was 5 years (4-7 years). Minimal change disease (MCD) was the most common histopathological diagnosis (n=54, 73%) followed by focal segmental glomerulosclerosis (FSGS) (n=13, 17.5%), mesangioproliferative glomerulonephritis(MesPGN) (n=6, 8.1%), IgA nephropathy (n=1, 1.4%). The median number of glomeruli included in each biopsy sample was 15. The median duration of treatment with CPO was 11 weeks (9 to 13 weeks), whereas the median duration of complete remission post-therapy was 13 months (7-23 months). A median timeframe of 17 months (13-24.2 months) lapsed between establishing the diagnosis of NS and initiating CPO treatment. Leucopenia was noted in six (8.1%) patients. The short-term outcome of relapsing SSNS can be improved with CPO and steroids, with minimum short-term side effects.

Hypertension and its severity in children with steroid sensitive nephrotic syndrome during remission.

Hypertension is not a typical feature of steroid sensitive nephrotic syndrome (SSNS) and the presence of persistent hypertension is suggestive of significant renal lesion. There is paucity of data regarding occurrence and severity of hypertension in SSNS in pediatric population during remission and was the main objective of this study. In addition, correlation with factors like family history, BMI, and lipid profile was studied. Cross-sectional study conducted at tertiary care center in India including 81 children of infrequent relapsing SSNS between 1 and 10years in remission and was off steroids. Grading and severity of hypertension were assessed. Statistical analysis was done using SPSS version 21.0. Median age of presentation was 5years, with male:female ratio of 1.3:1. Out of 81 infrequent relapsing SSNS children, 23.45% (19) had hypertension. Among those children with hypertension (n = 19), 73.68% (14) had positive family history compared to 32.25% (20) in those without hypertension. Positive correlation was found between BP and serum cholesterol and LDL. Of the hypertensive patients, 1 (5.26%) had fundus changes, 2 (10.52%) had features of left ventricular hypertrophy, and 13 (68.42%) had non-nephrotic range proteinuria. There is high incidence of hypertension in NS children during remission. Though significant positive correlation was found with positive family history of hypertension and deranged lipid profile highlighting possibility of essential hypertension in them, there is need for close active monitoring and management of hypertension in them as untreated cases may have significant target organ damage.

Urinary Neutrophil Gelatinase- Associated Lipocalin in Children with Idiopathic Nephrotic Syndrome: A Biomarker to Differentiate Between Steroid Sensitive and Resistant Forms of Disease

Background: Objectives of the study were to find out the ability of urinary neutrophil gelatinase- associated lipocalin (NGAL) as a biomarker to differentiate between steroid resistant nephrotic syndrome (SRNS) and steroid sensitive nephrotic syndrome (SSNS), and also to observe variation in levels, if any, between focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) in SRNS patients.Methods: The study included 63 patients of idiopathic nephrotic syndrome (19 SSNS in relapse, 19 SSNS in remission and 25 SRNS), aged 2.5-16 years, along with 17 controls. Urinary NGAL was measured by ELISA and the values were normalised with urinary creatinine.Results: Median urinary NGAL/creatinine level was significantly raised in SRNS as compared to SSNS relapse, SSNS remission and controls (p 18.3 ng/mg had sensitivity of 84%, specificity of 97.4% and area under the curve of 0.935 (p< 0.001, 95% confidence interval 0.871-0.998) to differentiate SRNS from SSNS patients. Median urinary NGAL/creatinine value was significantly raised in children with FSGS as compared to MCD (p=0.003) in SRNS patients. It had significant positive correlations with duration of illness (r=0.342, p=0.006), urine protein creatinine ratio (r=0.594, p< 0.001) and negative correlation with serum albumin (r=0.470, p<0.001).Conclusion: Urinary NGAL/creatinine level correlated with activity of the disease and it can distinguish not only SRNS from SSNS but also FSGS and MCD histopathological sub-types of SRNS in children.

Evaluation of interleukin-18 in children with steroid-sensitive nephrotic syndrome before and after using levamisole

Levamisole is often discussed as the first alternative to steroids. It is an antihelminthic drug that has been used for steroid-sensitive nephrotic syndrome (SSNS) for more than 20 years. Interleukin (IL)-18, a member of the IL-1 cytokine superfamily, is recognized as an important regulator of immune responses. The aim of the study was to investigate the IL-18 levels in serum from children with SSNS during relapse and remission after using levamisole or three months in a trial to test the efficacy of its action in reducing frequency of relapses in SSNS. This study was done on 23 children with frequently relapsing SSNS treated with levamisole besides steroids, then followed up three months; 16 males and seven females (mean age: 7.96 years and median 8 years). Clinical and laboratory assessments were done before starting therapy and after three months including cumulative dose of steroids and serum IL-18. We found that IL-18 level showed a significant elevation after three months of levamisole therapy compared to its level before initiation of levamisole therapy, with no relapses in these three months, no reported side effect, and significant reduction of cumulative dose of steroids. Levamisole effectiveness in reduction of relapses of SSNS may be due to resetting of the type 1/type 2 imbalance, proved by induction of IL 18 may be useful in the therapy.

Difficult-to-treat idiopathic nephrotic syndrome: established drugs, open questions and future options.

The idiopathic nephrotic syndrome in childhood can be classified according to the International Study of Kidney Disease in Children (ISKDC) based on the response to steroids. Typically, steroid-sensitive nephrotic syndrome (SSNS) is characterised by minimal changes in disease (MCD) histology, whereas in steroid-resistant nephrotic syndrome (SRNS) focal segmental glomerulosclerosis (FSGS) is the most prevalent lesion. Patients with SSNS may develop frequent relapses and/or steroid dependency, which can be difficult to treat. New studies confirm the value of calcineurin inhibitors (CNIs) and mycophenolic acid in preventing relapses of SSNS. Rituximab also plays an important role, but many questions regarding initial dosing, repetitions of courses, and long-term side effects remain unclear. SRNS, especially when unresponsive to treatment, can lead to chronic kidney disease. In particular, treatment with CNIs has improved the prognosis and recent data indicate that treatment can even be discontinued in many patients with full remission. In CNI-unresponsive SRNS, rituximab is less effective than in SSNS and the role of other biologicals (such as ofatumumab, abatacept, and others) remains unclear. A significant proportion of children with FSGS have genetic causes and most patients do not respond to immunosuppression, although individual patients with partial and even complete response have been documented. Future studies should evaluate treatments leading to long-term remission without maintenance immunosuppression in SSNS; in both genetic and immune-mediated SRNS, novel options to decrease the number of treatment-unresponsive patients seem mandatory, as they are at a high risk of developing end-stage renal disease.

Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children

About 80% to 90% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, around half relapse frequently, and are at risk of adverse effects from corticosteroids. Non-corticosteroid immunosuppressive medications are used to prolong periods of remission in these children; however, these medications have significant potential adverse effects. Currently, there is no consensus about the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. This is the third update of a review first published in 2001 and updated in 2005 and 2008. To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in relapsing SSNS in children. For this update we searched the Cochrane Renal Group's Specialised Register to June 2013. Randomised controlled trials (RCTs) or quasi-RCTs were included if they compared non-corticosteroid immunosuppressive medications with placebo, prednisone or no treatment, different non-corticosteroid immunosuppressive medications and different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). We identified 32 studies (1443 children) of which one study is still ongoing. In the 31 studies with data, risk of bias assessment indicated that 11 (37%) and 16 (53%) studies were at low risk of bias for sequence generation and allocation concealment respectively. Six (29%) studies were at low risk of performance and detection bias. Twenty seven (87%) and 19 (60%) studies were at low risk of incomplete and selective reporting respectively. Alkylating agents (cyclophosphamide and chlorambucil) significantly reduced the risk of relapse at six to 12 months (RR 0.43, 95% CI 0.31 to 0.60) and 12 to 24 months (RR 0.20, 95% CI 0.09 to 0.46) compared with prednisone alone. There was no significant difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no significant difference at one year between intravenous and oral cyclophosphamide (RR 0.99, 95% CI 0.76 to 1.29). Cyclosporin was as effective as cyclophosphamide (RR 1.07, 95% CI 0.48 to 2.35) and chlorambucil (RR 0.82, 95% CI 0.44 to 1.53) at the end of therapy while levamisole (RR 0.47, 95% CI 0.24 to 0.89) was more effective than steroids alone. However the effects of cyclosporin and levamisole were not sustained once treatment was stopped. In one small study cyclosporin significantly reduced the relapse rate compared with mycophenolate mofetil (MD 0.75, 95% CI 0.01 to 1.49). Limited data from a cross-over study suggested that cyclosporin was more effective than mycophenolate mofetil in maintaining remission. In steroid- and cyclosporin-dependent disease, rituximab significantly reduced the risk of relapse at three months compared with conventional therapy. Mizoribine and azathioprine were no more effective than placebo or prednisone alone in maintaining remission. Eight-week courses of cyclophosphamide or chlorambucil and prolonged courses of cyclosporin and levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Limited data indicate that mycophenolate mofetil and rituximab are valuable additional medications for relapsing SSNS. However clinically important differences in efficacy are possible and further comparative studies are still needed.

Early age at debut is a predictor of steroid-dependent and frequent relapsing nephrotic syndrome

The purpose of this study was to identify characteristics of patients with steroid-sensitive nephrotic syndrome (SSNS) that point to a high risk of frequent relapsing (FR) or steroid-dependent (SD) SSNS. A retrospective analysis of 54 consecutive patients with SSNS was performed. In this cohort, the incidence of idiopathic NS was 1.9/100,000, age at debut was 5.5 years, and the mean follow-up was 4.0 years. A total of 56% (30/54) of our patients were classified with FR/SD SSNS. FR/SD patients were significantly younger at debut than non-FR/SD patients (3.5 vs. 8.5 years, respectively; p < 0.002). Males were overrepresented in the FR/SD group (69 vs. 38%; p = 0.03). No differences were found in terms of haematuria, hypoalbuminaemia, or days to achieve remission. In total, 31 and 23 patients were on a 6 + 6-week (pred-long) and 4 + 4-week (pred-short) steroid treatment regimen, respectively. There was a reduction in the number of FR/SD patients in the pred-long group relative to the pred-short group (38 vs. 80%, respectively). In the pred-long group, the 12 FR/SD patients were younger than the 19 non-FR/SD patients (4.4 +/- 3.1 vs. 8.4 +/- 4.1 years; p<0.005). Low age at debut and male gender was associated with a high risk of SD/FR in this unselected series of SSNS patients despite the prolongation of the steroid course at debut of SSNS.

High-sensitivity C-reactive protein (hs-CRP) level in children with nephrotic syndrome

The aim of this study was to assess the serum concentration of high-sensitivity C-reactive protein (hs-CRP) in children with nephrotic syndrome (NS) treated with prednisone and cyclosporine A (CyA). Patients were divided into three groups: (I) 20 NS children (aged 4-14 years) in relapse and examined twice, (A) before treatment and (B) after proteinuria regression (a 3-4 week course of prednisone therapy); (II) 20 children with steroid-dependent or steroid-resistant NS, treated with CyA, also examined twice, (D) before treatment with CyA, (E) 6 months after therapy. A control group (C) consisted of 20 healthy children. Serum hs-CRP level was determined by a nephelometric method with a Behring Nephelometer 100 Analyzer, Dade Behring. The results showed that median hs-CRP concentration was the highest in children with relapsing steroid-sensitive NS before treatment (IA). After proteinuria regression (IB), the hs-CRP level had decreased and did not differ from that of healthy controls (C) (P>0.05). In group II, before CyA administration (IID), the level of hs-CRP was normal, but it had increased after 6 months of treatment (IIE) up to a level six-times higher than that of the control group (P<0.01). We concluded that, in children with steroid-sensitive nephrotic syndrome in relapse, the serum hs-CRP level is increased but returns to normal after 3-4 weeks of glucocorticoid treatment. In children chronically treated with CyA due to NS, serum hs-CRP level increases significantly during the therapy.

Circannual variation in the onset and relapse of steroid-sensitive nephrotic syndrome

Idiopathic nephrotic syndrome is the most common form of nephrotic syndrome in children, but little is known about the etiology of the disease. To obtain new insights into the etiology of the disease, we studied circannual patterns of initial episodes and relapses of steroid-sensitive nephrotic syndrome (SSNS). From 1986 to 2003, there were 45 children with SSNS in our hospital, and they experienced 43 relapses during that period. Initial episodes of SSNS were found to show significant circannual variation with an autumn peak both by Roger's test and Freedman's test, and the circannual pattern was more obvious in patients with high serum IgE levels. Chronological evaluation by means of Fourier analysis showed a clear circannual pattern. In contrast, relapses of SSNS showed circannual variation with a spring peak, which was a result of a high frequency of relapses after upper respiratory infections in January. These results suggest that circannual variation in initial episodes of SSNS might be associated with allergic predisposition, whereas circannual variation in relapses might be associated with preceding upper respiratory infections.