Rituximab in children with resistant idiopathic nephrotic syndrome.
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ABSTRACT:
SUBMITTER: Magnasco A
PROVIDER: S-EPMC3358759 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC6868353 | biostudies-literature
Project description:Drug resistant idiopathic nephrotic syndrome (DRNS) remains a therapeutic dilemma. In this pilot study, the efficacy of the new fully humanised, anti-CD20 monoclonal antibody ofatumumab was tested in 4 children with persistence of proteinuria for at least 12 months in spite of a full drug approach (including rituximab). We used a low-dose 2-infusion ofatumumab model (300+700 mg/1.73 m(2) 2 weeks apart) using specified premedication. Transient normalisation of proteinuria (persisting for 2 months) was achieved in 1 child while another presented stable remission after 12 months; both had normal renal function. The outcome was not modified in the remaining 2 children presenting an impaired renal function. These results demonstrate that low-dose ofatumumab may induce remittance of proteinuria in children with a long story of DRNS and normal renal function. Further studies are needed to test whether higher doses of ofatumumab can also modify proteinuria in patients with impaired renal function.
| S-EPMC4577716 | biostudies-literature
Project description:The pathogenesis of nephrotic syndrome is unclear. However, the efficacy of rituximab, a B cell-depleting antibody, in nephrotic syndrome suggests a pathogenic role of B cells. In this retrospective study, we determined by flow cytometry levels of B and T cell subpopulations before and after rituximab infusion in 28 pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome. At baseline, patients had lower median percentages of transitional and mature B cells than age-matched healthy controls (P<0.001). Rituximab induced full depletion of B cells (<1% of lymphocytes). At 1 year, most patients exhibited complete total and mature B cell recovery, whereas memory B cell subsets remained significantly depleted. Total T cell concentration did not change with rituximab, whereas the CD4(+)/CD8(+) T cell ratio tended to increase. Fourteen patients relapsed within 24 months, with a median follow-up of 11.2 months (interquartile range, 8-17.7 months). We observed no difference at baseline between nonrelapsing and relapsing patients in several clinical parameters and cell subset concentrations. Reconstitution of all memory B cell subpopulations, number of immunosuppressive drugs, and dose of tacrolimus during the last 4 months of follow-up were predictive of relapse in univariate Cox regression analysis. However, only delayed reconstitution of switched memory B cells, independent of immunosuppressive treatment, was protective against relapse in multivariate (P<0.01) and receiver operator characteristic (P<0.01 for percentage of lymphocytes; P=0.02 for absolute count) analyses. Evaluation of switched memory B cell recovery after rituximab may be useful for predicting relapse in patients with nephrotic syndrome.
| S-EPMC4884116 | biostudies-literature
Project description:The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ?2 recurrences over the previous year and were in steroid-induced remission for ?1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.
| S-EPMC3968490 | biostudies-literature
Project description:The pathogenesis of idiopathic nephrotic syndrome is not completely understood. We postulate that cytokine gene polymorphisms may influence susceptibility or clinical course in Idiopathic Nephrotic Syndrome. Polymorphisms of IL-4, IL-6, and TNF-α cytokines were investigated in 150 children with Idiopathic Nephrotic Syndrome and 569 healthy controls by using polymerase chain reaction and restriction fragment length polymorphism. On comparing patient with controls strong association were found for IL-6, TNF-α and IL-4 at allelic level (IL-6-G174C (G vs. C): P = <0.001; OR = 6.33, TNF-α-G308A (G vs. A): P = <0.001; OR = 1.99, IL-4-C590T (C vs. T): P = 0.048; OR = 1.38). Further when SR group was compared with SS group significant association was found at genotypic level in all the studied genetic polymorphisms. Studied cytokine gene polymorphisms may influence susceptibility to idiopathic nephrotic syndrome and might affect steroid response in INS patients.
| S-EPMC3162962 | biostudies-literature
Project description:Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell-mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.
| S-EPMC4822672 | biostudies-literature
Project description: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.
| S-EPMC3816123 | biostudies-literature
Project description:BackgroundRituximab (RTX) has recently been introduced as a second-line therapy for nephrotic syndrome in children. Studies show that RTX given during the nephrotic state may be less effective than treatment during a non-nephrotic state, possibly due to loss of RTX in the urine.Case-diagnosis/treatmentWe describe a 10-year-old boy with steroid-resistant nephrotic syndrome (SRNS) treated with RTX during a phase of active non-selective proteinuria. The serum half-life of RTX in this patient was less than 1 day compared to 20 days in patients without protein losses. Urinary clearance was at least 25 %, compared to approximately 0 % in control patients. However, RTX loss in the urine, as well as in pleural effusion and ascites, only partly explains the rapid drop in the serum RTX concentration of this patient.ConclusionsSerum half-life of RTX can be extremely short, partly due to excessive urinary losses in therapy-resistant nephrotic syndrome with non-selective proteinuria, as seen in our patient. These findings may help to explain the poor results of RTX treatment in patients with active proteinuria.
| S-EPMC4483248 | biostudies-literature
Project description:BackgroundUrinary exosomal miRNAs are gaining increasing attention for their potential as ideal non-invasive biomarkers for kidney diseases; however, little is known about their diagnostic ability for paediatric nephrotic syndrome (NS). This study explored the clinical value of urinary exosomal miRNAs for paediatric idiopathic NS.MethodsUrine samples were collected from 129 NS children and 126 age-/sex-matched healthy controls. The miRNA profile of urinary exosomes was analysed by high-throughput Illumina sequencing via synthesis (SBS) technology followed by verification with a quantitative reverse-transcription polymerase chain reaction (RT-qPCR) assay arranged in two independent cohorts. Additionally, paired urine samples from 65 of these patients were collected before and after treatment.FindingsThe Illumina SBS identified 30 markedly increased urinary exosomal miRNAs in NS children compared with controls (? 5-fold, P?<?.05). Fifteen miRNAs were selected for further investigation, of which 5 (miR-194-5p, miR-146b-5p, miR-378a-3p, miR-23b-3p and miR-30a-5p) were verified by RT-qPCR to be significantly and steadily increased in NS (> 3-fold, P?<?.01) and markedly reduced during the clinical remission period (P?<?.001). Moreover, the concentrations of miR-194-5p and miR-23b-3p were significantly positively correlated with the urine protein content and were markedly higher in the high urine protein group than in the low urine protein group (P?<?.001 and P?<?.01, respectively).InterpretationsWe identified 5 altered urinary exosomal miRNAs in NS children with disease progression and treatment. These urinary exosomal miRNAs could be promising and non-invasive potential biomarker candidates for diagnosing, monitoring and stratifying paediatric NS. FUND: National Natural Science Foundation of China; Fund of State Key Laboratory of Analytical Chemistry for Life Science; National Basic Research Programme of China; Foundation of Jiangsu Provincial Medical Youth Talent.
| S-EPMC6355644 | biostudies-literature
Project description:Tregs infusion reverts proteinuria and reduces renal lesions in most animal models of nephrotic syndrome (i.e. Buffalo/Mna, Adriamycin, Promycin, LPS). IL2 up-regulates Tregs and may be an alternative to cell-therapy in this setting. To evaluate a potential role of IL2 as Tregs inducer and proteinuria lowering agent in human nephrotic syndrome we treated 5 nephrotic patients with 6 monthly cycles of low-dose IL2 (1x106 U/m2 first month, 1.5x106 U/m2 following months). The study cohort consisted of 5 children (all boys, 11–17 years) resistant to all the available treatments (i.e. steroids, calcineurin inhibitors, mycophenolate, Rituximab). Participants had Focal Segmental Glomerulosclerosis (3 cases) or Minimal Change Nephropathy (2 cases). IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses. Circulating Tregs were stably increased (>10%) during the whole study period in 2 cases while were only partially modified in the other two children who started with very low levels and partially responded to single IL2 Proteinuria and renal function were not modified by IL2 at any phase of the study. We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs. This drug may not be able to lower proteinuria or affect renal function in children with idiopathic nephrotic syndrome. We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome.ClinicalTrials.gov NCT02455908.
| S-EPMC4587361 | biostudies-literature