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.

Adult survivors of childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome treated with cyclosporine: a long-term single-center experience.

BACKGROUND: Although evidence has confirmed that cyclosporine (CS) is efficacious against childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome (SD/SRNS), some patients may continue to relapse during adulthood. However, predictive factors for adult active disease and kidney complications, such as chronic kidney disease (CKD) and hypertension, in this cohort remain unknown. METHODS: We conducted a retrospective study on the long-term outcomes of 81 young adults with childhood-onset SD/SRNS treated with CS. The primary endpoint was the probability of active disease into adulthood. The secondary endpoint was the probability of developing kidney complications. RESULTS: At the last follow-up (median age, 23.2 years; median disease duration, 15.8 years), 44 adult patients (54%) continued to have active disease, whereas 16 patients developed CKD or hypertension, respectively. The proportion of patients developing kidney complications was similar between the active disease and long-term remission groups. Young age at NS onset and history of relapse during the initial CS (median, 31 months) were independent predictive factors for active disease. Acute kidney injury at NS onset, focal segmental glomerulosclerosis, and irreversible CS nephrotoxicity were identified as risk factors for the development of CKD, whereas older age was identified as a risk factor for the development of CKD and hypertension. CONCLUSIONS: More than 50% of adult survivors treated with CS continued to have active disease, and each 20% developed CKD or hypertension. A long-term follow-up is necessary for patients with SD/SRNS to identify the development of kidney complications later in adulthood that can be attributed to prior disease and CS treatment in childhood, irrespective of disease activity. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Pioglitazone enhances proteinuria reduction in complicated pediatric nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is a common pediatric kidney disease, yet current treatments for complicated NS are only partially effective and have significant toxicity. There is no Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved safe and effective treatment for NS. Thiazolidinediones (TZDs) have been shown to reduce proteinuria in both diabetic and non-diabetic kidney disease and in preclinical studies to directly protect podocytes from injury and reduce proteinuria. Here, we report on the potential utility of the addition of the TZD pioglitazone (PIO) to enhance proteinuria reduction in 8 children and young adults with steroid dependent NS and steroid resistant NS. METHODS: Clinical data were analyzed in comparable time periods before and after the addition of PIO to their medical regimens. Eight NS patients with minimal change NS (n = 2), focal segmental glomerulosclerosis (FSGS) (n = 4), or collapsing FSGS (n = 2) were evaluated. RESULTS: Prior to PIO initiation, all children and young adults had already received multiple immunosuppressive medications (mean = 3.75). Five of eight patients (63%; "Responders") had notable proteinuria reduction within 1 month of PIO initiation (62% reduction; P = 0.04) and normalization within 6 months (97% reduction; P = 0.04). PIO-related benefits among the responders included notable increases in serum albumin (2.5 to 3.7 g/dl; P = 0.08), dramatic reductions in hospitalizations for IV albumin infusions and diuresis (11 to 0; P < 0.01), and considerable reduction in total immunosuppression (43% reduction; P > 0.1). Importantly, no patients experienced any adverse events attributable to PIO during a total of 136 patient-months of treatment. CONCLUSIONS: While confirmatory safety and efficacy studies are needed, these findings suggest pioglitazone (a non-immunosuppressive drug) may be useful to enhance proteinuria reduction in some children and young adults with complicated NS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Predictive factors of long-term disease remission after rituximab administration in patients with childhood-onset complicated steroid-dependent nephrotic syndrome: a single-center retrospective study.

BACKGROUND: Despite the fact that rituximab (RTX)-associated adverse events may be relatively frequent in younger patients, recent studies have reported RTX as a suitable first-line steroid-sparing agent for maintaining remission in children with steroid-dependent nephrotic syndrome (SDNS). However, the impact of age at RTX initiation on the long-term outcome remains unknown in this cohort. METHODS: We retrospectively reviewed the clinical course of 61 patients with complicated SDNS who received a single dose of RTX (375 mg/m2) followed by maintenance immunosuppressive agents (IS) from January 2008 to March 2021. In patients who achieved > 12 months of prednisolone-free remission, IS tapering within 6 months was tried to achieve. The primary endpoint was the probability of achieving long-term treatment-free remission at the last follow-up. RESULTS: After RTX initiation, 52 patients (85.2%) relapsed after a median of 665 days, and 44 patients (72.1%) received additional RTX doses (total, 226 infusions). At the last follow-up (median observation period, 8.3 years; median age, 18.3 years), 16 patients (26.2%) achieved long-term remission. Multivariate analysis showed that older age at RTX initiation was the independent predictive factor for achieving long-term remission (odds ratio, 1.25; p < 0.05). The proportion of those who achieved long-term remission was significantly higher in patients aged ≥ 13.5 years than in those aged < 13.5 years at RTX initiation (52.6 vs 14.3%, p < 0.05). Persistent severe hypogammaglobulinemia did not develop in older children (≥ 13.5 years) at RTX initiation. CONCLUSION: For older children with complicated SDNS, RTX appeared to be a suitable disease-modifying therapy without persistent adverse events.

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.

Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome.

BACKGROUND: Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient). RESULTS: TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. CONCLUSIONS: Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome.

Immune dysregulation plays a key role in the pathogenesis of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS). However, in contrast with evidence from the pediatric series, no major B- or T-cell alterations have been described for adults. In these patients, treatment with rituximab allows safe discontinuation of steroids, but long-term efficacy is variable, and some patients experience NS relapses after B cell reconstitution. In this study, we aimed to determine disease-associated changes in the B and T cell phenotype of adult patients with SDND/FRNS after steroid-induced remission. We also investigated whether any of these changes in immune cell subsets could discriminate between patients who developed NS relapses after steroid-sparing treatment with rituximab from those who did not. Lymphocyte subsets in SDNS/FRNS patients (n = 18) were compared to those from patients with steroid-resistant NS (SRNS, n = 7) and healthy volunteers (HV, n = 15). Before rituximab, SDND/FRNS patients showed increased frequencies of total and memory B cells, mainly with a CD38-negative phenotype. Within the T-cell compartment, significantly lower levels of FOXP3+ regulatory T cells (Tregs) were found, mostly due to a reduction in CD45RO+ memory Tregs compared to both SRNS and HV. The levels of CD45RO+ Tregs were significantly lower at baseline in patients who relapsed after rituximab (n = 9) compared to patients who did not (n = 9). In conclusion, patients with SDND/FRNS displayed expansion of memory B cells and reduced memory Tregs. Treg levels at baseline may help identify patients who will achieve sustained remission following rituximab infusion from those who will experience NS relapses.

Anti-rituximab antibodies in pediatric steroid-dependent nephrotic syndrome.

BACKGROUND: Rituximab is a chimeric anti-CD20 monoclonal antibody that induces sustained remission in children with steroid-dependent nephrotic syndrome. However, there is no consensus on the optimal regimen and monitoring of rituximab. In other autoimmune diseases, anti-rituximab antibodies (ARA) have been reported in 10-40% of patients, but their clinical relevance remains unclear. In nephrotic syndrome, data are scarce. METHODS: We report a single-center retrospective study with immuno- and pharmacological monitoring of rituximab treatment in children with frequent relapsing (FR) or steroid-dependent nephrotic syndrome (SDNS). We analyzed the monthly monitoring of 24 children, receiving a dose of rituximab (375 mg/m2) between December 2017 and April 2018 at the Pediatric Nephrology Department of Robert-Debré hospital, Paris. RESULTS: ARA were detected in 7/24 patients (29%), sometimes after the first infusion of rituximab. ARA were present at baseline in two patients previously treated with rituximab. Both displayed no B-cell depletion. ARA were also reported in 5/22 patients during follow-up, with antibodies always detected in the first month following B-cell recovery. An incomplete CD19+CD20- B-cell depletion at M1 (5-25/mm3) and low serum rituximab levels was predictive of developing ARA. The development of de novo ARA during follow-up was not associated with shorter B-cell depletion. CONCLUSIONS: This study shows that ARA are frequent in children with FR/SDNS and that close immuno- and pharmacological monitoring may help personalizing rituximab treatment in patients needing repeated injections.

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.

Clinical efficacy of mycophenolate mofetil versus levamisole therapy in frequently relapsing and steroid dependent childhood nephrotic syndrome - A retrospective comparative analysis.

BACKGROUND: Children with frequently relapsing (FR) or steroid dependent (SD) nephrotic syndrome (NS) often develop side effects of corticosteroids. Various steroid-sparing agents are in practice, but only a few studies exist so far which have compared the safety and efficacy of these two commonly used agents. METHODS: We did a retrospective medical records review of children with FRNS or SDNS who had levamisole or mycophenolate mofetil (MMF) as a steroid-sparing agent with a minimum follow-up period of 12 months. The aim was to compare the course of our patients on MMF and levamisole. Our primary objective was to determine the number of children in sustained remission and those with the infrequently relapsing course on levamisole and MMF and, the median time to relapse in months in the two groups. The secondary objective was to compare time to first relapse and number of relapses in FRNS and SDNS group children on MMF and levamisole. RESULTS: A total of 88 children (34% female) with diagnosis FR/SDNS (44 each) were included in the study. Thirty-nine patients took levamisole, while 49 received MMF therapy. The median age of presentation at the relapsing course was 4.2 years. The proportion of children with sustained remission or infrequent relapsing (IFR) course on MMF was 73.6%, compared to 48.71% on levamisole (p-value .015). In addition, the median time to first relapse was 12 months (24, 1.5) and 4.5 months (24, 1) on respective medications. CONCLUSION: Clinical outcome was superior in the MMF group than levamisole, especially in SDNS patients, and also MMF was more efficacious in maintaining sustained remission.

Efficacy of rituximab therapy in children with nephrotic syndrome: a 10-year experience from an Iranian pediatric hospital.

BACKGROUND: There are controversy results in the optimal management of children with steroid-dependent and steroid-resistant nephrotic syndrome (SDNS, SRNS). This study aimed to determine the efficacy and safety of rituximab (RTX) in these pediatric patients. METHODS: Medical records of 1-18-year-old Iranian children with SDNS (n = 26) and SRNS (n = 22) with a follow-up for at least 24 months were included from 2009 to 2019. The short- and long-term responses to RTX were respectively evaluated to determine the random protein-to-creatinine ratio after 6 and 24 months and classified as complete (CR) and partial (PR) remission or no response. RESULTS: Male patients (n = 26) were slightly predominate. The median age of patients at the time of RTX therapy was 8.6 ± 4.01 years. At the end of the 6-month follow-up, CR and PR occurred in 23 (47.9%) and 12 (25%) patients, respectively. Of 23 patients with CR, 18 (69.2%) and 5(22.7%) had SDNS and SRNS, respectively (p < 0.005). However, only 18 (37.5%) of patients after 24 months had been in CR. No significant difference in the CR rate was found between the two groups. RTX was more effective when administered during the proteinuria-free period (p = 0.001). CONCLUSION: In the short term, RTX significantly was efficient in inducing complete or PR in SDNS and SRNS patients. However, the favorable response rate in a long-term follow-up was insignificantly lower between the two groups.

Predictors of Treatment Response and Long-Term Outcomes in Young Children with Steroid-Dependent Nephrotic Syndrome Treated with High-Dose Mizoribine as First-Line Steroid-Sparing Agent.

Mizoribine may be a safe and effective treatment for children with steroid-dependent nephrotic syndrome (SDNS). However, predictors of treatment response and long-term outcomes after mizoribine discontinuation remain unknown. We retrospectively reviewed the clinical course of 22 children aged ≤ 10 years (median age, 5.3 years) with SDNS who received high-dose mizoribine as the initial steroid-sparing agent (SSA). Mizoribine was administered at a single daily dose of 10 mg/kg (maximum, 300 mg/day) after breakfast. The dose was adjusted to maintain 2-h post-dose mizoribine levels of > 3 µg/mL and was tapered off after 12 months of steroid-free remission. Patients who regressed to SDNS were switched from mizoribine to other SSAs. The primary endpoint was probability of survival without regression to SDNS after mizoribine initiation. Ten patients were able to discontinue SDNS (response group), whereas twelve were switched from mizoribine to other SSAs (non-response group) during a median observation period of 6.0 years after mizoribine. The steroid-dependent dose prior to mizoribine was significantly lower in the response group than in the non-response group (p < 0.05). The Kaplan-Meier analysis revealed that the probability of regression-free survival was significant higher in patients with steroid-dependent dose of < 0.25 mg/kg/day than in those with steroid-dependent dose of ≥ 0.25 mg/kg/day (p < 0.05). During a median follow-up of 5.5 years after mizoribine discontinuation, all but one patient did not develop SDNS. High-dose mizoribine may be an attractive treatment option as initial SSA in young children with low steroid-dependent dose for improved long-term outcomes.

Human or Chimeric Monoclonal Anti-CD20 Antibodies for Children with Nephrotic Syndrome: A Superiority Randomized Trial.

BACKGROUND: The chimeric anti-CD20 monoclonal antibody rituximab is effective in steroid-dependent and calcineurin inhibitor-dependent forms of nephrotic syndrome, but many patients relapse at 1 year. Because ofatumumab, a fully human anti-CD20 monoclonal antibody, has a more extended binding site and higher affinity to CD20 compared with rituximab, it might offer superior efficacy in these patients. METHODS: We designed a single-center randomized clinical trial to compare the long-term efficacy of ofatumumab versus rituximab in children and young adults with nephrotic syndrome maintained in remission with prednisone and calcineurin inhibitors. We randomized 140 children and young adults (aged 2-24 years) to receive intravenous ofatumumab (1.50 mg/1.73 m2) or rituximab (375 mg/m2). After infusions, oral drugs were tapered and withdrawn within 60 days. The primary outcome was relapse at 1 year, which was analyzed following the intent-to-treat principle. The secondary endpoint was relapse within 24 months from infusion, on the basis of urine dipstick and confirmed by a urine protein-to-creatinine ratio <200. RESULTS: At 12 months, 37 of 70 (53%) participants who received ofatumumab experienced relapse versus 36 of 70 (51%) who received rituximab (odds ratio [OR], 1.06; 95% confidence interval [95% CI], 0.55 to 2.06). At 24 months, 53 of 70 (76%) participants who received ofatumumab experienced relapse, versus 46 of 70 (66%) who received rituximab (OR, 1.6; 95% CI, 0.8 to 3.3). The two groups exhibited comparable B cell subpopulation reconstitution and did not differ in adverse events. CONCLUSIONS: A single dose of ofatumumab was not superior to a single dose of rituximab in maintaining remission in children with steroid-dependent and calcineurin inhibitor-dependent nephrotic syndrome. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT02394119) and https://www.clinicaltrialsregister.eu/ctr-search/search (2015-000624-28).

Associations Between Cessation of Second-Line Therapies and Relapse Rates of Childhood Refractory Minimal-Change Nephrotic Syndrome: A Single-Center, Retrospective Chart Review.

Background: Most patients (≥85%) with minimal-change nephrotic syndrome (MCNS) respond to corticosteroid treatment. However, about 10% to 20% of patients with MCNS have steroid-resistant nephrotic syndrome and 25% to 43% of patients have steroid-dependent nephrotic syndrome or frequent-relapse steroid-sensitive nephrotic syndrome. Patients with refractory MCNS are treated with various second-line therapies. Objectives: This study aimed to evaluate the associations between the use of various second-line therapies and relapse rates in Chinese patients with childhood refractory MCNS. Methods: In this study, patients with childhood nephrotic syndrome renal biopsy proved to be "minimal change" from a single tertiary-care center between January 2002 and July 2018 were identified. A Total of 56 medical charts of patients treated with 1 of these second-line immunosuppressors: cyclophosphamide (CYC), mycophenolate mofetil (MMF), or tacrolimus (TAC) were reviewed. Patients were divided into CYC (n = 24), MMF (n = 20), and TAC (n = 12) groups according to the second-line therapy administered. Baseline characteristics, immune status, immunocomplex deposition in the renal tissue, and treatment outcomes were analyzed. Results: The ratio of patients with steroid-resistant nephrotic syndrome and steroid-dependent nephrotic syndrome in the CYC, MMF, and TAC groups did not differ significantly (P = 0.721). The immunofluorescence assay did not show any significant differences in immunocomplex deposition identified in renal biopsy specimens among the 3 groups. The rate of steroid-free remission in the TAC group (75%) was higher than that in the MMF (55%) and CYC (25%) groups (P = 0.012). At the last follow-up, two-thirds of children in the TAC group had a relapse following discontinuation of therapy. In the TAC group, patients for whom steroids were withdrawn had significantly higher levels of immunoglobulin G at the onset of nephrotic syndrome than those for whom steroids were continued (P = 0.017). In the MMF group, children with relapse had a significantly higher percentage of CD16+CD56+-positive cells than those without relapse (P = 0.042). The relapse rate after treatment discontinuation was significantly different among the 3 groups (P = 0.035). Notably, the relapse rate after treatment discontinuation in the CYC group was lower than those in the other 2 groups (P = 0.035). Conclusions: In this small population of Chinese patients with childhood refractory MCNS, the relapse rate following TAC therapy was higher than that following MMF or CYC therapy. Different proportions of CD16+CD56+-positive cells might be associated with relapse rates in patients with MCNS receiving MMF treatment. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome.

BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS) is, in most patients, a chronic disease with 80% experiencing at least one relapse after first flare. B cell depletion using rituximab is effective in preventing relapse in steroid-dependent (SDNS) patients but fails to maintain long-term remission following B cell recovery, possibly due to development of autoreactive long-lived plasma cells. We investigated sequential combination of antiCD20 antibody targeting all B cell subsets, and antiCD38 antibody with high plasma cell cytotoxicity in patients with uncontrolled SDNS after failure of one or several attempts at B cell depletion. METHODS: Fourteen patients with median disease duration 7.8 years received 1000 mg/1.73 m2 obinutuzumab followed by 1000 mg/1.73 m2 daratumumab 2 weeks later. Oral immunosuppression was discontinued within 6 weeks, and biological monitoring performed monthly until B cell recovery. RESULTS: Median age at treatment was 11.0 [IQR 10.4-14.4] years. B cell depletion was achieved in all patients, and B cell reconstitution occurred in all at median 9.5 months after obinutuzumab injection. After median follow-up 20.3 months (IQR 11.5-22.6), 5/14 patients relapsed including 4 within 100 days following B cell repletion. Relapse-free survival was 60% at 24 months from obinutuzumab infusion. Mild infusion reactions were reported in 3/14 patients during obinutuzumab and 4/14 during daratumumab infusions. Mild transient neutropenia (500-1000/mm3) occurred in 2/14 patients. Intravenous immunoglobulins were given to 12/14 patients due to hypogammaglobulinemia. Low IgA and IgM levels were noted in 8 and 14 patients, respectively. No severe infection was reported. CONCLUSION: Global antiB cell strategy combining obinutuzumab and daratumumab induces prolonged peripheral B cell depletion and remission in children with difficult-to-treat SDNS.

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 in children with steroid sensitive nephrotic syndrome: in quest of the optimal regimen.

Rituximab has emerged as an effective and important therapy in children with complicated frequently relapsing and steroid-dependent nephrotic syndrome to induce long-term disease remission and avoid steroid toxicities. The optimal rituximab regimen is not totally well defined, and there are many varying practices worldwide. We will in this review describe how patient factors, rituximab dose, and use of maintenance immunosuppression affect treatment outcomes. Specifically, low-dose rituximab without concomitant immunosuppression is associated with shorter relapse-free duration while other regimens have comparable outcomes. Patients with more severe disease generally have worse response to rituximab. Although rituximab appears to be generally safe, there are growing concerns of chronic hypogammaglobulinemia and impaired immunity especially in young children. Reliable prognostications and biomarkers for guiding subsequent treatments to avoid excessive treatments are yet to be identified. In this review, we will outline the, as we see it, best approach of rituximab in childhood steroid sensitive nephrotic syndrome at the present state of knowledge.

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.

Rituximab in treatment of collapsing FSGS-A case series.

BACKGROUND: Collapsing focal segmental glomerulosclerosis (cFSGS) is an aggressive glomerular disease presenting as a nephrotic syndrome that has lower rates of remission with conventional immunosuppressive therapy and rapidly progresses to end-stage-renal-disease (ESRD). We report eight cases of HIV-negative cFSGS treated with rituximab. METHODS: The current report is a retrospective case series of cFSGS treated with rituximab from January 2011 to March 2020, at varying phases of the disease. RESULTS: Eight out of the 70 cFSGS patients received rituximab. The median age of patients was 30 years (IQR 24.25-37.5); five patients were males. The median serum creatinine, mean serum albumin and median 24 hours urinary protein at presentation was 0.9 (IQR 0.66-1.27) mg/dL, 2.95 ± 1.15 g/dL, 4.87 (IQR 1.64-5.75) g/day, respectively. Two patients were steroid-resistant, one steroid and tacrolimus dependent, one steroid and cyclosporine dependent, two steroids and tacrolimus resistant, one steroid, tacrolimus, cyclophosphamide, mycophenolate mofetil resistant and one steroid-resistant and tacrolimus dependent before rituximab therapy. Rituximab was given either as targeted therapy (after an initial dose of 375 mg/m2 ; patients having CD-19 levels >5/µL or >1% at 1 month received additional low-dose [100 mg] of rituximab), or weekly regimen. Five patients received CD-19 targeted rituximab; three received weekly doses of 375 mg/m2 , cumulative doses being 820 ± 228.03 mg, and 1800 ± 721.11 mg, respectively. At the end of median follow-up of 15 months, five (62.5%) patients were in remission (three partial, two complete remissions), two (25%) were resistant to therapy; one (12.5%) progressed to ESRD. CONCLUSION: Rituximab is reasonably safe and achieves/maintains remission in 60% of cFSGS cases.