Feasibility of discontinuing immunosuppression in children with idiopathic nephrotic syndrome.

BACKGROUND: Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed. METHODS: This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded. RESULTS: Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8 months (IQR 24.6-71.2 months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3 years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use. CONCLUSIONS: Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants. TRIAL REGISTRATION: Not applicable.

Association between the time of initial relapse and subsequent relapses in patients with childhood-onset idiopathic nephrotic syndrome.

BACKGROUND: Nephrotic syndrome relapse within 6 months is a known risk factor for steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome (SDNS/FRNS), but the risk of early development of SDNS/FRNS and initiation of immunosuppression therapy remains unknown. METHODS: Patients with childhood-onset idiopathic nephrotic syndrome who had the first relapse within 6 months were enrolled. We analyzed the relationship between the time of the first relapse or the time of initial remission and incidence of SDNS/FRNS or initiation of immunosuppression therapy. RESULTS: Forty-five patients were enrolled. Twenty out of 23 patients (87%) with the first relapse within 30 days after discontinuing initial steroid therapy experienced a second relapse within 30 days after discontinuing steroid therapy. Additionally, most patients in this group (96%) experienced a second relapse within 6 months after the onset and were diagnosed as SDNS/FRNS at this time. In this group, the incidence of SDNS/FRNS development within 6 months was 96%. In contrast, the incidence of SDNS/FRNS development within 6 months was 18% in patients with the first relapse more than 30 days after steroid discontinuation. The incidence of initiation of immunosuppressive agents within 6 months was 83% in the former group and 14% in the latter group. CONCLUSIONS: Most patients with the first relapse within 30 days after discontinuing steroid therapy developed SDNS/FRNS and were administered immunosuppressive agents within 6 months. Thus, it might be reasonable to start immunosuppression therapy in this group without waiting for the second relapse.

IgA nephropathy in a boy with frequently relapsing nephrotic syndrome.

A Japanese boy developed nephrotic syndrome (NS) and had microscopic hematuria at 8 years old. Renal biopsy was performed. Light microscopy study revealed mesangial proliferation and all immunofluorescent stains (including IgA) were negative, so he was diagnosed with non-IgA diffuse mesangial proliferation (DMP). Complete remission was achieved at 13 days after the initiation of oral prednisolone, and hematuria also disappeared 3 days later, but the patient developed frequently relapsing nephrotic syndrome. Cyclosporine A (CyA) was introduced at 10 years old, and there were no relapses between then and when it was discontinued at 12 years old. A second renal biopsy revealed minimal change without CyA nephrotoxicity. However, there was repeated relapse of NS after discontinuation, so CyA was reintroduced 8 months later, and NS remained in remission thereafter. Microscopic hematuria appeared at 13 years old, however, with gross hematuria appearing at the time of infection. A third renal biopsy revealed mesangial proliferation with IgA-dominant deposition, so the patient was diagnosed with IgA nephropathy. Currently (14 years old), CyA treatment has been discontinued and the patient is undergoing lisinopril therapy for IgA nephropathy, but there are still relapses of NS. To the best of our knowledge, there have been no previous reports of a patient with non-IgA DMP at the onset of NS who had later development of IgA nephropathy. The patient showed non-IgA DMP at the onset, suggesting that NS with non-IgA DMP and IgA nephropathy has some common pathophysiology. Treatment for NS, such as PSL and/or CyA treatment, may suppress the clinical manifestation of late IgA nephropathy.

Incidence of relapse and frequently relapsing/steroid-dependent nephrotic syndrome in Chinese children with steroid-sensitive nephrotic syndrome: A cohort study.

AIM: This study aimed to investigate the incidence of relapse and FR/SDNS in Chinese children with SSNS and to develop clinical prediction models for relapse and FR/SDNS. METHODS: This retrospective cohort study involved 339 newly onset SSNS patients between 2006 and 2016. The incidence of relapse and FR/SDNS were estimated using the Kaplan-Meier method. Prediction models were constructed based on Cox proportional-hazards regression. RESULTS: The median follow-up time was 8.7 years. The cumulative incidence of relapse at 1-, 2-, and 5-year was 51.0%, 62.5%, and 66.6%. The cumulative incidence of FR/SDNS at 1-, 2-, and 5-year was 18.4%, 29.0%, and 32.9%. The final prediction model for first relapse included four variables (serum albumin, triglycerides, IgM, and time to first remission). The model's discriminative ability was low (Harrell's C index = 0.62). The final prediction model for FR/SDNS included four variables (serum albumin, lipoprotein(a), time to first remission, and time to first relapse). The discrimination and calibration of the prediction model for FR/SDNS were acceptable (Harrell's C index = 0.73, Brier score at 1- and 2-year were 0.11 and 0.17). CONCLUSION: The first relapse and FR/SDNS mainly occurred in the first 2 years after initial SSNS onset. The prediction model for relapse developed using common clinical parameters performed poorly, while the prediction model for FR/SDNS might be useful.

Forecast and verification of the active compounds and latent targets of Guyuan decoction in treating frequently relapsing nephrotic syndrome based on network pharmacology.

BACKGROUND: Our study majorly utilizes network pharmacology combined with molecular docking to explore the latent active components and associated pivotal targets of Guyuan Decoction (GYD) in the treatment of frequently relapsing nephrotic syndrome (FRNS). METHODS: All active components and latent targets of GYD were retrieved from TCMSP database. The target genes for FRNS in our research were obtained from the GeneCards database. The drug-compounds-disease-targets (D-C-D-T) network was established using Cytoscape 3.7.1. STRING database was applied to observe the protein interaction. Pathway enrichment analyses (GO and KEGG) were conducted in R software. Moreover, molecular docking was employed to further validate the binding activity. MPC-5 cells were treated with adriamycin to mimic FRNS in vitro and to determine the effects of luteolin on modeled cells. RESULTS: A total of 181 active components and 186 target genes of GYD were identified. Meanwhile, 518 targets related to FRNS were also revealed. Based on the intersection using a Venn diagram, 51 common latent targets were recognized to be associated with active ingredients and FRNS. Additionally, we identified the biological processes and signaling pathways involved in the action of these targets. Molecular docking analyses illustrated that AKT1 and CASP3 interacted with luteolin, wogonin, and kaempferol, respectively. Moreover, luteolin treatment enhanced the viability but inhibited the apoptosis of adriamycin-treated MPC-5 cells via regulating AKT1 and CASP3. CONCLUSION: Our study forecasts the active compounds, latent targets, and molecular mechanisms of GYD in FRNS, which helps us to understand the action mechanism of GYD in FRNS comprehensive treatment.

IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome.

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.

Therapeutic trials in difficult to treat steroid sensitive nephrotic syndrome: challenges and future directions.

Steroid sensitive nephrotic syndrome is a common condition in pediatric nephrology, and most children have excellent outcomes. Yet, 50% of children will require steroid-sparing agents due to frequently relapsing disease and may suffer consequences from steroid dependence or use of steroid-sparing agents. Several steroid-sparing therapeutic agents are available with few high quality randomized controlled trials to compare efficacy leading to reliance on observational data for clinical guidance. Reported trials focus on short-term outcomes such as time to first relapse, relapse rates up to 1-2 years of follow-up, and few have studied long-term remission. Trial designs often do not consider inter-individual variability, and differing response to treatments may occur due to heterogeneity in pathogenic mechanisms, and genetic and environmental influences. Strategies are proposed to improve the quantity and quality of trials in steroid sensitive nephrotic syndrome with integration of biomarkers, novel trial designs, and standardized outcomes, especially for long-term remission. Collaborative efforts among international trial networks will help move us toward a shared goal of finding a cure for children with nephrotic syndrome.

Efficacy of rituximab versus tacrolimus in difficult-to-treat steroid-sensitive nephrotic syndrome: an open-label pilot randomized controlled trial.

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. A higher resolution version of the Graphical abstract is available as Supplementary information.

Rituximab treatment in pediatric patients with steroid-dependent nephrotic syndrome: A tertiary hospital.

BACKGROUND: Corticosteroids have had a central role in the treatment of nephrotic syndrome. The management of these patients who become dependent to steroids is complex, involving different immunosuppressive drugs patterns. The monoclonal antibody anti CD20, Rituximab, is likely to have beneficial effects in cases of steroid-dependent nephrotic syndrome patients with no easy resolution, even when we cannot make a statement about the specific role in the impact. We bring our personal experience in pediatric patients treated with this medication during the last years, to provide a thorough overview and useful information about the role of Rituximab in this pathology. METHODS: Retrospective study in patients with steroid-dependent idiopathic nephrotic syndrome controlled in the division of Pediatric Nephrology of a Spanish tertiary hospital in those patients who had received at least one treatment cycle of Rituximab, at any moment along the evolution of the disease. RESULTS: The study involved 8 patients. All of them previously received immunosuppressive therapy. The Rituximab were administered as an intravenous infusion, in a dose of 375 mg/m2, and all doses were administered in a period during which the disease was in remission. The depletion of lymphocytes B (CD19, 0%) were confirmed after the first dose of Rituximab except for one, with a lymphocyte count of 1%. The period of depletion lasts 10,3 months (median; range 6,5-16 months), and only one of the patients registered a relapse of the disease in this period. A reduction of relapses suffered by patients has been shown after the treatment began (3,6 relapses/year in the previous year to the start of the treatment versus 0,1 relapses/year during the first year post-rituximab). The relapse-free survival in the first year reached 83,3% in patients who suffered more than one relapse (75% of patients), and without a relapse after the treatment began in 2 cases. One or more drugs could be removed in 87,5% of patients after the first cycle of rituximab. After the rituximab treatment, we reached a 96,5% decrease in the corticosteroids doses administered (28,5 mg/m2/day during the 3 months pre-treatment versus 1 mg/m2/day in the last 3 months of patient monitoring). Not a significant observed adverse effect attributed to the drug after the post-rituximab monitoring period (median 46,5 months, range 5-97 months). CONCLUSION: The favorable results reported after rituximab treatment in our patients seems to confirm the effectiveness of this drug in the steroid-dependent nephrotic syndrome, making that therapeutic option into consideration and legitimating the use of the drug in complex cases involving pediatric patients. Even so, it seems recommendable to design pertinent studies to clarify, among others, the optimum regimen of the treatment (dose, interval and cycles), clinical repercussion and potential adverse effects in long terms.

Incidence and risk factors of rituximab-associated hypogammaglobulinemia in patients with complicated nephrotic syndrome.

BACKGROUND: Hypogammaglobulinemia is a major adverse event after rituximab treatment; however, the precise incidence and risk factors are unclear in complicated steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS) patients. METHODS: This was a single-center, retrospective, observational study. Patients who received a single dose of rituximab for complicated SDNS or FRNS between February 2007 and May 2019 were enrolled. Serum IgG levels were plotted, and their trends were evaluated after rituximab treatment. The incidence of transient and persistent hypogammaglobulinemia was examined, and risk factors were calculated by multivariate analysis using logistic regression. RESULTS: We enrolled 103 patients who received 238 single doses of rituximab. Hypogammaglobulinemia was observed in 58.4% of the patients at least once after a single dose of rituximab treatment and 22.3% developed persistent hypogammaglobulinemia. Serum IgG levels gradually increased during B-cell depletion, and patients with low serum IgG levels at rituximab treatment had persistent hypogammaglobulinemia. Repeated courses of rituximab treatment increased the incidence of hypogammaglobulinemia. A past history of steroid-resistant nephrotic syndrome (SRNS) (odds ratio [OR] = 10.02; 95% confidence interval [CI] = 2.65-37.81; P < 0.001) and low serum IgG levels at rituximab treatment (OR = 7.63; 95% CI = 2.10-27.71; P = 0.002) was significantly associated with hypogammaglobulinemia in multivariate analysis. CONCLUSIONS: Hypogammaglobulinemia is a frequent adverse event after rituximab treatment, although IgG levels slightly increase during B-cell depletion. Low serum IgG levels at rituximab treatment and a past history of SRNS are significant risk factors for the development of hypogammaglobulinemia after rituximab treatment.

Belimumab for the treatment of children with frequently relapsing nephrotic syndrome: the BELNEPH study.

BACKGROUND: Effectiveness of rituximab in pediatric idiopathic nephrotic syndrome suggests that B cells play a pathogenic role. We tested safety and efficacy of the B-cell-modulating agent belimumab in frequently relapsing nephrotic syndrome (FRNS). METHODS: An open-label, prospective, single-arm pilot study (EUDRACT 2017-003839-11) was designed to treat 10 children with FRNS with i.v. belimumab for 12 months. Prednisone was tapered/stopped. Safety, number of relapses, cumulative prednisone dose and B-cell subset "levels" are referred to both B cell subset and immunoglobulin. RESULTS: Five patients were enrolled, and four reached the primary 6-month endpoint. Of these, two completed the 12-month endpoint. Three patients experienced ≥2 relapses while on belimumab, requiring additional immunosuppression. Compared to the 6 months before belimumab treatment, the mean number of relapses (1.4 vs. 2, p=0.21) and the mean cumulative prednisone dose (1.86 vs. 2.62 g/m2, p=0.17) were not significantly reduced during the 6 months on belimumab. This study was terminated by the steering committee after the interim evaluation because belimumab failed to show clear benefits to counterbalance the inconvenience of monthly i.v. infusion. During follow-up, total and mature-naïve B cells decreased, while no change in memory B-cells was observed. Serum immunoglobulins remained stable. No infusion reaction was observed. CONCLUSIONS: Short-term treatment with belimumab in pediatric FRNS was well tolerated. The number of patients was too small to draw conclusions on efficacy. Nonetheless, we did not observe clear improvements. The burden of monthly in-hospital i.v. infusions outweighed potential benefits. Persistence of circulating memory B cells supports their pathogenic role in the disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Mycophenolate Mofetil in the Treatment of Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome in Children: A Meta-Analysis.

Objectives: This meta-analysis aims to evaluate the efficacy and safety of the mycophenolate mofetil (MMF) in the treatment of steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing nephrotic syndrome (FRNS) in children. Methods: We searched for the studies especially the randomized controlled trials in PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wan Fang database. The data were analyzed by Review Manager 5.3 software. We used the GRADE pro-Guideline Development Tool online software to evaluate the quality of evidence. Results: Finally, we identified 620 studies, of which we included five randomized controlled trials and one prospective cohort study with 447 children. The results showed the following: (1) the relapse-free survival rate within 1 year-the MMF group was superior to the levamisole group [ratio difference (RD) = 0.13, 95% CI (0.02, 0.24), P = 0.02] but not to the calcineurin inhibitors (CNIs) group [RD = -0.27, 95%CI (-0.40, -0.14), P < 0.0001]; (2) the number of relapses within 1 year-the MMF group was less than that in the CNIs and levamisole group [mean difference (MD) = -0.26, 95%CI (-0.45, -0.08), P = 0.005]; (3) the cumulative prednisone dosage-the MMF group was lower than that in the control group [standardized mean difference (SMD) = -0.32, 95%CI (-0.53, -0.11), P = 0.003]; (4) incidence of adverse reactions-there was no significant difference between the MMF group and the control group [RD = 0.02, 95%CI (-0.04, 0.09), P = 0.46]. Conclusion: The therapy of mycophenolate mofetil in the treatment of SDNS or FRNS in children has a certain advantage in reducing the number of relapses and cumulative prednisone dosage within 1 year when compared with the CNIs and levamisole. However, due to the limited quantity and quality of the included studies, the conclusions above need to be confirmed by more high-quality randomized controlled trials.

Pediatric idiopathic steroid-sensitive nephrotic syndrome: diagnosis and therapy -short version of the updated German best practice guideline (S2e) - AWMF register no. 166-001, 6/2020.

Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts of the world. Children with steroid-sensitive nephrotic syndrome (SSNS) generally have a good prognosis regarding the maintenance of normal kidney function even in the case of frequent relapses. The course of SSNS is often complicated by a high rate of relapses and the associated side effects of repeated glucocorticoid (steroid) therapy. The following recommendations for the treatment of SSNS are based on the comprehensive consideration of published evidence by a working group of the German Society for Pediatric Nephrology (GPN) based on the systematic Cochrane reviews on SSNS and the guidelines of the KDIGO working group (Kidney Disease - Improving Global Outcomes).

Rituximab treatment for difficult-to-treat nephrotic syndrome in children: a multicenter, retrospective study

Background/aim: This study aimed to evaluate the efficacy of rituximab in children with difficult-to-treat nephrotic syndrome, considering the type of disease (steroid-sensitive or ­resistant) and the dosing regimen. Materials and methods: This multicenter retrospective study enrolled children with difficult-to-treat nephrotic syndrome on rituximab treatment from 13 centers. The patients were classified based on low (single dose of 375 mg/m2) or high (2-4 doses of 375 mg/m2) initial dose of rituximab and the steroid response. Clinical outcomes were compared. Results: Data from 42 children [20 steroid-sensitive (frequent relapsing / steroid-dependent) and 22 steroid-resistant nephrotic syndrome, aged 1.9­17.3 years] were analyzed. Eleven patients with steroid-sensitive nephrotic syndrome (55%) had a relapse following initial rituximab therapy, with the mean time to first relapse of 8.4 ± 5.2 months. Complete remission was achieved in 41% and 36% of steroid-resistant patients, with the median remission time of 3.65 months. At Year 2, eight patients in steroid-sensitive group (40%) and four in steroid-resistant group (18%) were drug-free. Total cumulative doses of rituximab were higher in steroid-resistant group (p = 001). Relapse rates and time to first relapse in steroid-sensitive group or remission rates in steroid-resistant group did not differ between the low and high initial dose groups. Conclusion: The current study reveals that rituximab therapy may provide a lower relapse rate and prolonged relapse-free survival in the steroid-sensitive group, increased remission rates in the steroid-resistant group, and a significant number of drug-free patients in both groups. The optimal regimen for initial treatment and maintenance needs to be determined.

[Rituximab treatment in pediatric patients with steroid-dependent nephrotic syndrome: a tertiary hospital]. / Tratamiento con rituximab en pacientes pediátricos con síndrome nefrótico córtico-dependiente. Experiencia en un hospital terciario.

BACKGROUND: Corticosteroids have had a central role in the treatment of nephrotic syndrome. The management of these patients who become dependent to steroids is complex, involving different immunosuppressive drugs patterns. The monoclonal antibody anti CD20, Rituximab, is likely to have beneficial effects in cases of steroid-dependent nephrotic syndrome patients with no easy resolution, even when we cannot make a statement about the specific role in the impact. We bring our personal experience in pediatric patients treated with this medication during the last years, to provide a thorough overview and useful information about the role of Rituximab in this pathology. METHODS: Retrospective study in patients with steroid-dependent idiopathic nephrotic syndrome controlled in the division of Pediatric Nephrology of a spanish tertiary hospital in those patients who had received at least one treatment cycle of Rituximab, at any moment along the evolution of the disease. RESULTS: The study involved 8 patients. All of them previously received immunosuppressive therapy. The Rituximab were administered as an intravenous infusion, in a dose of 375 mg/m2, and all doses were administered in a period during which the disease was in remission. The depletion of lymphocytes B (CD 19%) were confirmed after the first dose of Rituximab except for one, with a lymphocyte count of 1%. The period of depletion lasts 10.3 months (median; range 6.5-16 months), and only one of the patients registered a relapse of the disease in this period. A reduction of relapses suffered by patients has been shown after the treatment began (3.6 relapses/year in the previous year to the start of the treatment vs. 0.1 relapses/year during the first year post-rituximab). The relapse-free survival in the first year reached 83.3% in patients who suffered more than one relapse (75% of patients), and without a relapse after the treatment began in 2 cases. One or more drugs could be removed in 87.5% of patients after the first cycle of rituximab. After the rituximab treatment, we reached a 96.5% decrease in the corticosteroids doses administered (28.5 mg/m2/day during the 3 months pre-treatment vs. 1 mg/m2/day in the last 3 months of patient monitoring). Not a significant observed adverse effect attributed to the drug after the post-rituximab monitoring period (median 46.5 months, range 5-97 months). CONCLUSION: The favorable results reported after rituximab treatment in our patients seems to confirm the effectiveness of this drug in the steroid-dependent nephrotic syndrome, making that therapeutic option into consideration and legitimating the use of the drug in complex cases involving pediatric patients. Even so, it seems recommendable to design pertinent studies to clarify, among others, the optimum regimen of the treatment (dose, interval and cycles), clinical repercussion and potential adverse effects in long terms.

Prophylactic rituximab administration in children with complicated nephrotic syndrome.

BACKGROUND: Rituximab is effective for maintaining remission in patients with complicated nephrotic syndrome, although a history of steroid-resistant nephrotic syndrome (SRNS) is a risk factor for early relapse. We investigated the efficacy of prophylactic rituximab treatment for maintaining remission after B cell recovery. METHODS: Patients with complicated steroid-dependent or frequently relapsing nephrotic syndrome with history of SRNS who received a single dose of rituximab (375 mg/m2) and continued immunosuppressive agents were enrolled in this retrospective study. Patients were divided into two groups: a prophylaxis group, which received additional rituximab treatment at B cell recovery and a non-prophylaxis group. The relapse-free period from the last rituximab infusion (the second treatment in prophylaxis group and the first treatment in non-prophylaxis group) was compared between two groups using the Kaplan-Meier method, and risk factors for early relapse were calculated using multivariate analysis by Cox proportional hazards model. RESULTS: Sixteen patients in the prophylaxis group and 45 in the non-prophylaxis group were enrolled. Fifty-percent relapse-free survival after the last rituximab treatment was 667 days in the former and 335 days in the latter (p = 0.001). Multivariate analysis showed that additional rituximab treatment was the only significant negative factor for early relapse, with a hazard ratio of 0.40 (p = 0.02). Fifty-percent relapse-free survival after B cell recovery was much longer in the prophylaxis group (954 vs. 205.5 days, p = 0.003). CONCLUSIONS: Additional rituximab treatment at B cell recovery can maintain prolonged remission even after B cell recovery in patients with complicated nephrotic syndrome with history of SRNS.

Retos terapéuticos en el síndrome nefrótico idiopático / Therapeutic challenges in the idiopathic nephrotic syndrome

El diagnóstico, evaluación y tratamiento del síndrome nefrótico en el niño data de los tiempos de Hipócrates. Sin embargo, en la actualidad algunos pacientes con la enfermedad siguen siendo un reto terapéutico para el médico. Nos proponemos examinar en la literatura reciente, distintas propuestas o protocolos de tratamiento y las nuevas drogas que pueden utilizarse en la atención al paciente con esta enfermedad. Los protocolos de tratamiento varían con relativa frecuencia y las drogas, tanto en los síndromes nefróticos recaedores frecuentes, corticodependientes o corticorresistentes, no garantizan en muchas ocasiones la curación del paciente. Cuando fracasan los esteroides se pueden utilizar agentes alquilantes, inhibidores de la calcineurina, antiproliferativos, anticuerpos monoclonales y otros fármacos, pero existen pacientes que no tienen remisión de la proteinuria con ninguno de estos tratamientos. Por sus características evolutivas, algunos pacientes con síndrome nefrótico idiopático siguen siendo un reto para el médico que trata de evitar su evolución hacia la pérdida de la función renal. A pesar de todos los avances en la atención del niño con síndrome nefrótico, desde el descubrimiento de los esteroides, antibióticos, diuréticos e inmunosupresores, en la actualidad no sabemos exactamente cuál es el mejor tratamiento en las formas resistentes del síndrome nefrótico idiopático en niños(AU)

Diagnosis, evaluation and treatment of nephrotic syndrome in children dates from Hypocrate times. However, nowadays some patients with this disease are still a therapeutic challenge for physicians. The aim of this work is to search in recent literature different proposals or treatment protocols, and new drugs that can be used in the care of patients with this disease. Treatment protocols vary with relative frequency and drugs, as well as in frequent relapsing nephrotic, corticodependent or corticoresistant syndromes, do not guarantee in many ocassions the cure of the patient. When steroids fail, alkylanting agents, calcineurin depressants, antispreading, monoclonal antibodies and other drugs can be ussed; but there are patients who do not have remission of proteinuria with any of these treatments. Due to their evolutive characteristics, some patients with idiopathic nephrotic syndrome are still a challenge for the physicians who try to avoid its evolution toward the loss of renal function. Although all the advances in the care of children with nephrotic syndrome due to the discover of steroids, antibiotics, diuretics and immunosupressive drugs, nowadays we do not exactly know which is the best treatment for the resistant types of idiopathic nephrotic syndrome in children(AU)

Clinical Response and Pattern of B cell Suppression with Single Low Dose Rituximab in Nephrology.

Background: There is no consensus regarding dose and frequency of rituximab in nephrology with extrapolation of doses used in treating lymphoproliferative disorders. There are no guidelines on targeting initial and subsequent doses on the basis of CD19+ B cells. Methods: Initially, 100 mg rituximab was given to 42 adults with steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS), idiopathic membranous nephropathy (MN), and high-immunologic-risk kidney transplantation. Absolute and percentage levels of CD19 B cells and clinical status were assessed at baseline, days 30, 90, and 180, and at 1 year. Subsequent doses of rituximab were on the basis of CD19 B cell reconstitution and clinical response. Results: CD19 B cell percentage decreased from 16.3 ± 7.6 to 0.3 ± 0.3 (P≤0.001), 1.9 ± 1.7 (P≤0.001), and 4.0 ± 4.5 (P=0.005) by 30, 90, and 180 days, respectively. Suppression of CD19 B cell count below 1% at days 30, 90, and 180 was seen in 40 of 42 (95.2%), 18 of 42 (42.9%), and 7 of 42 (16.7%) patients, respectively. Of 30 with SDNS and FRNS followed up for 1 year, 29 (96.7%) went into remission at day 30. Remission was sustained in 23 (76.6%) at day 180 and 21 (70%) at 1 year. There was a significant decrease (P<0.001) in the dose of steroids needed to maintain remission at 180 days after rituximab (0.27 ± 0.02 mg/kg to 0.02 ± 0.00 mg/kg). CD19 B cell percentage at 90 days correlated with relapse (P=0.001; odds ratio 1.42; 95% confidence interval, 1.25 to 2.57). Eighteen (60%) required an additional dose. Of five with MN, four achieved remission by 6 months, which was sustained in three by 1 year. Of the seven kidney transplant recipients, two had antibody-mediated rejections, although CD19 B cells were suppressed even at 1 year. Conclusions: Low-dose rituximab induces sustained depletion of CD19 B cells for up to 90 days. Its role in preventing relapses in SDNS, FRNS, MN, and rejection needs further study.

Pathologic tonsillar findings similar to IgA nephropathy and the role of tonsillectomy in a patient with nephrotic syndrome.

BACKGROUND: The pathological findings of tonsils in IgA nephropathy include the expansion of T-cell nodules around lymphoid follicles and abnormal reticulation of the crypt epithelium in contrast to chronic tonsillitis. Recently, several studies have reported that regulatory T cells play an important role in the maintenance of self-tolerance, an abnormality that is involved in the onset of nephrotic syndrome (NS). We encountered a patient of 28-year-old male with frequently relapsing nephrotic syndrome (FRNS) and chronic tonsillitis whose tonsils demonstrated pathological findings similar to those of IgA nephropathy. CASE PRESENTATION: A patient had developed NS at the age of 5 years, and was pathologically diagnosed with minimal change disease (MCD), for which he received various immunosuppressive agents as treatment for recurrence. Because tonsillitis often triggers the recurrence of NS, a tonsillectomy was performed for chronic tonsillitis at the age of 25 years. Immunohistochemical staining of his tonsils showed the expansion of CD4 positive lymphocytes around the lymphoid follicles and abnormal reticulation of the crypt epithelium. The number of peripheral blood CD4+CD25+ regulatory T cells increased, and the frequency of relapses decreased after tonsillectomy. CONCLUSION: A similar self-tolerance abnormality exists in NS and IgA nephropathy; therefore, tonsillectomy might become a novel therapeutic approach for FRNS to redress the unbalanced self-tolerance and to remove the tonsillar focal infection. Further studies are necessary to verify the clinical efficiency of tonsillectomy for FRNS with recurrent episodes triggered by tonsillitis.

Study protocol: multicenter double-blind, randomized, placebo-controlled trial of rituximab for the treatment of childhood-onset early-stage uncomplicated frequently relapsing or steroid-dependent nephrotic syndrome (JSKDC10 trial).

BACKGROUND: Eighty percent of children with idiopathic nephrotic syndrome respond well to steroid therapy, but up to 50% of patients with steroid-sensitive nephrotic syndrome exhibit frequently relapsing (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Several studies identified the chimeric anti-CD20 monoclonal antibody rituximab as an effective treatment for patients with complicated FRNS/SDNS. Recent studies suggested that rituximab could also be a first-line treatment for early-stage uncomplicated FRNS/SDNS, although further studies are required to confirm its efficacy and safety. METHODS/DESIGN: We are conducting a multicenter, double-blind, randomized placebo controlled trial to investigate the efficacy and safety of rituximab for the treatment of childhood-onset early-stage uncomplicated FRNS/SDNS. Patients will be allocated to receive two 375 mg/m2 doses (maximum dose: 500 mg) of either rituximab or placebo. Investigators are permitted to request the disclosure of a subject's allocation code if he or she exhibits treatment failure. Additionally, if placebo-treated subjects display early relapse (a sign of treatment failure), they have the option to receive rituximab in an unblinded phase. The primary endpoint is relapse-free survival during the observation period. DISCUSSION: The results will provide important data on the use of rituximab for patients with uncomplicated FRNS/SDNS. In the future, rituximab treatment will enable most patients with uncomplicated FRNS/SDNS to discontinue or reduce steroid therapy without relapse, and it is possible that rituximab could represent an immunosuppressive therapy for these diseases. TRIAL REGISTRATION: This trial was prospectively registered to the JMACCT Clinical Trials Registry on September 6, 2018 (Trial ID: JMA-IIA00380 ).