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AbstractObjectiveTo determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse.DesignDouble blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis.Setting125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres.Participants237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome.InterventionsChildren were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more).Main outcome measuresThe primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat.ResultsNo significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval −0.005 to 0.037) and cost savings (difference −£1673 ($2160; €1930), 95% confidence interval −£3455 to £109).ConclusionsClinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life.Trial registrationISRCTN16645249; EudraCT 2010-022489-29.

In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1–5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor–sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.

Nephrotic syndrome (NS) is associated with increased risk of venous thromboembolism (VTE). Guidelines suggest prophylactic anticoagulants to patients with high risk of thrombosis and low risk of bleeding, but the evidence behind this is poor. This study aims to investigate the effectiveness and risks of prophylactic anticoagulants (PAC) and investigate risk factors for VTE and bleeding in NS. A retrospective medical records study including adults with NS, biopsy proven glomerular disease in the county of Västernorrland, Sweden. Outcomes were VTE, bleeding and death. Patients divided into PAC- and no PAC group were compared using Fisher's exact test. Patient time was divided into serum/plasma(S/P)-albumin intervals (<20g/L and ≥20g/L) and VTE- and bleeding rates were calculated. In 95 included NS patients (PAC = 40, no PAC = 55), 7 VTE (7.4%) and 17 bleedings (18%) were found. Outcomes didn't differ significantly between the PAC and no PAC group. Time with S/P-albumin <20g/L conferred higher rates/100 years of VTE (IRR 21.7 (95%CI 4.5-116.5)) and bleeding (IRR 5.0 (1.4-14.7)), compared to time with S/P-albumin>20g/L. Duration of severe hypoalbuminemia (S/P-albumin <20g/L) in NS is a risk factor for both VTE and bleeding. There is a need for randomized controlled studies regarding the benefit of PAC in NS as well as risk factors of thrombosis and bleeding in NS.

BackgroundNutritional status assessment in children with nephrotic syndrome (NS) is critical for identifying patients who are at risk of protein-energy wasting (PEW) and for determining their nutritional needs and monitoring nutritional intervention outcomes.MethodsIn a case–control study, we enrolled 40 children (age range: 2–16 years) with NS and 40 apparently healthy children (age and sex-matched) as a control group. Anthropometric data, as well as demographic, clinical, and laboratory data, were collected. A dietary intake assessment using a 3-day food intake record was done, and the quadriceps rectus femoris thickness (QRFT) and quadriceps vastus intermedius thickness (QVIT) were assessed using B-mode ultrasound and compared between both groups.ResultsChildren with NS had lower QRFT and QVIT measurements than control groups (p < 0.001). Inadequacy in protein intake occurred in 62.5% and 27.5% of the NS and control groups, respectively (p = 0.002). The thickness of the rectus and vastus muscles by ultrasound was significantly associated with the percentage of protein intake (p < 0.001). The ROC curve revealed that the best cutoff value of QRFT for the prediction of the patient at risk of malnutrition was ≤ 1.195 with an area under curve of 0.907, with p < 0.001.ConclusionIn children with NS, skeletal muscle ultrasound is a simple and easy-to-use bedside technique for the identification of patients at risk of malnutrition.

Background Rituximab and tacrolimus are therapies reserved for patients with frequently relapsing or steroid-dependent nephrotic syndrome who have failed conventional steroid-sparing agents. Given their toxicities, demonstrating non-inferiority of rituximab to tacrolimus may enable choice between these medications. Methods This investigator-initiated, single-center, open-label, pilot randomized controlled trial examined the non-inferiority of two doses of intravenous (IV) rituximab given one-week apart to oral therapy with tacrolimus (1:1 allocation), in maintaining sustained remission over 12 months follow-up, in patients with difficult-to-treat steroid-sensitive nephrotic syndrome, defined as frequently relapsing or steroid-dependent disease that had failed ≥ 2 steroid-sparing strategies. Secondary outcomes included frequency of relapses, proportion with frequent relapses, time to relapse and frequent relapses, and adverse events (CTRI/2018/11/016342). Results Baseline characteristics were comparable for 41 patients randomized to receive rituximab ( n  = 21) or tacrolimus ( n  = 20). While 55% of patients in each limb were in sustained remission at 1 year, non-inferiority of rituximab to tacrolimus was not demonstrated (mean difference 0%; 95% CI – 30.8%, 30.8%; non-inferiority limit – 20%; P  = 0.50). Frequent relapses were more common in patients administered rituximab compared to tacrolimus (risk difference 30%, 95% CI 7.0, 53.0, P  = 0.023). Both groups showed similar reductions in relapse rates and prednisolone use. Common adverse events were infusion-related with rituximab and gastrointestinal symptoms with tacrolimus. Conclusions Therapy with rituximab was not shown to be non-inferior to 12-months treatment with tacrolimus in maintaining remission in patients with difficult-to-treat steroid-sensitive nephrotic syndrome. Frequent relapses were more common with rituximab. While effective, both agents require close monitoring for adverse events. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information .

There are limited data on the relative efficacy and safety of calcineurin inhibitors and alkylating agents for idiopathic steroid-resistant nephrotic syndrome in children. To clarify this, we compared tacrolimus and intravenous cyclophosphamide therapy in a multicenter, randomized, controlled trial of 131 consecutive pediatric patients with minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis, stratified for initial or late steroid resistance. Patients were randomized to receive tacrolimus for 12 months or 6-monthly infusions of intravenous cyclophosphamide with both arms receiving equal amounts of alternate-day prednisolone. The primary outcome of complete or partial remission at 6 months, based on spot urine protein to creatinine ratios, was significantly higher in children receiving tacrolimus compared to cyclophosphamide (hazard ratio 2.64). Complete remission was significantly higher with tacrolimus (52.4%) than with cyclophosphamide (14.8%). The secondary outcome of sustained remission or steroid-sensitive relapse of nephrotic syndrome at 12 months was significantly higher with tacrolimus than cyclophosphamide. Treatment withdrawal was higher with cyclophosphamide, chiefly due to systemic infections. Compared to cyclophosphamide, 3 patients required treatment with tacrolimus to achieve 1 additional remission. Thus, tacrolimus and prednisolone are effective, safe, and preferable to cyclophosphamide as the initial therapy for patients with steroid-resistant nephrotic syndrome.

Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with prednisone 2 mg/kg/day or 60 mg/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 ± 3 years and mean disease duration 2.2 ± 1.8 years. The children were randomized to receive 2, 1.5, or 1 mg/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 ± 3.3 days; the difference between the 1.5 and 2 mg/kg/day groups was statistically significant. One patient each in the 1 mg/kg/day and the 1.5 mg/kg/day groups failed to respond and were switched to 2 mg/kg/day, leading to a response after 3 and 10 days, respectively. Mean cumulative prednisone doses in the 3 groups were 45.5 ± 3.4, 42.7 ± 25.9, and 24.9 ± 7.4 mg/kg, respectively (P < 0.05).Conclusion: In the present study, treatment of childhood steroid sensitive nephrotic syndrome relapse with prednisone 1–1.5 mg/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 1–1.5 mg/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.

Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85–90% of patients attain complete remission of proteinuria within 4–6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70–80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given.

Background Cross-sectional studies of children with prevalent nephrotic syndrome (NS) have shown 25-vitamin D (25(OH)D) deficiency rates of 20–100 %. Information on 25(OH)D status in incident patients or following remission is limited. This study aimed to assess 25(OH)D status of incident idiopathic NS children at presentation and longitudinally with short-term observation. Methods Multicenter longitudinal study of children (2–18 years old) from 14 centers across the Midwest Pediatric Nephrology Consortium with incident idiopathic NS. 25(OH)D levels were assessed at diagnosis and 3 months later. Results Sixty-one children, median age 5 (3, 11) years, completed baseline visit and 51 completed second visit labs. All 61 (100 %) had 25(OH)D < 20 ng/ml at diagnosis. Twenty-seven (53 %) had 25(OH)D < 20 ng/ml at follow-up. Fourteen (28 %) children were steroid resistant. Univariate analysis showed that children prescribed vitamin D supplements were less likely to have 25(OH)D deficiency at follow-up (OR 0.2, 95 % CI 0.04, 0.6). Steroid response, age, and season did not predict 25(OH)D deficiency. Multivariable linear regression modeling showed higher 25(OH)D levels at follow-up by 13.2 ng/ml (SE 4.6, p  < 0.01) in children supplemented with vitamin D. Conclusions In this incident idiopathic NS cohort, all children at diagnosis had 25(OH)D deficiency and the majority continued to have a deficiency at 2–4 months. Supplemental vitamin D decreased the odds of 25(OH)D deficiency at follow-up, supporting a role for supplementation in incident NS.

Background Body surface area (BSA)-based prednisolone dosing for childhood nephrotic syndrome (NS) leads to higher cumulative prednisolone doses than body weight (BW)-based dosing. The clinical effects of this higher dosage have not been evaluated in prospective studies. Methods This parallel-group open-label randomized clinical trial enrolled 100 children with idiopathic NS, to receive BW-based ( n  = 50) or BSA-based ( n  = 50) prednisolone dosing by block randomization in a 1:1 ratio. The time taken for remission, relapse rate per 6 months, and adverse effects of steroids were analyzed in both groups. Results There was no significant difference in the time taken for remission in the BW group versus the BSA group (median (IQR) 7 (4.5–9) versus 5.5 (4–8) days; p  = 0.082); similar results were observed on subgroup analysis in new-onset and infrequently-relapsing NS (IFRNS). The cumulative prednisolone dosage during the enrolment episode was higher in the BSA group. The incidence of hypertension was higher ( p  = 0.048) in the BSA group on per-protocol analysis. The relapse rates in the two groups per 6 months on follow-up were comparable. Conclusions Clinical outcomes with BW-based dosing are equivalent to BSA dosing-related outcomes, although cumulative prednisolone doses are lower in the former. The practice of BW-based calculations for prescribing prednisolone in NS is a reasonable approach.