Dataset Information

A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

ABSTRACT: 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.

SUBMITTER: Bonanni A

PROVIDER: S-EPMC4587361 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

Bonanni Alice A Bertelli Roberta R Rossi Roberta R Bruschi Maurizio M Di Donato Armando A Ravani Pietro P Ghiggeri Gian Marco GM

PloS one 20150928 9

<h4>Unlabelled</h4>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 stud ...[more]

PMID: 26413873

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Project description:To assess whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid (GC)-resistant from GC-sensitive idiopathic nephrotic syndrome (INS), patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), we measured the methylation level of NLRP3 promoter in DNA from peripheral blood cells of 10 adult patients with GC-resistant FSGS already in hemodialysis and 18 patients with GC-sensitive INS (13 MCD/5 FSGS) and in 21 pediatric patients with INS with MCD/FSGS before starting any treatment. Association of NLRP3 inflammasome with GC resistance was recapitulated in vitro in monocytic cell lines (THP-1 and U937). In both adults and pediatric patients, NLRP3 promoter methylation was significantly reduced in GC-resistant compared with GC-sensitive patients. Indeed, NLRP3 methylation distinguished GC-resistant and GC-sensitive patients (area under the receiver operating characteristic curve [AUROC] 86.7% in adults, p = 0.00019, and 73.5% in children, p = 0.00097). NLRP3 knock-down augmented sensitivity to GCs in THP-1 cells, whereas NLRP3 inflammasome activation lowered GC receptor concentration, increasing GC resistance in U937 cells. Our results uncovered a new biological mechanism by which patients with INS may acquire GC resistance, that could be used in future as a novel noninvasive diagnostic tool. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Approximately 80% of patients with idiopathic nephrotic syndrome (INS) respond to glucocorticoids, with the remaining 20% being steroid-resistant. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid-resistant from glucocorticoid (GC)-sensitive INS. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ In both adults and children, NLRP3 promoter methylation was significantly reduced in leukocytes of patients with GC-resistant compared with GC-sensitive INS. NLRP3 inflammasome activation lowered GC receptor concentration and augmented GC resistance, whereas NLRP3 knockdown increased sensitivity to GCs in cell lines representative of monocytes (U937 and THP1). HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ Our findings uncovered a new biological mechanism whereby patients with INS may develop resistance to GCs that could be used in the future as a novel noninvasive diagnostic tool.

Project description:BackgroundNephrotic syndrome is one of the chronic illnesses in the pediatric age group. The aim of this study was to assess the oral health of patients with steroid-sensitive idiopathic nephrotic syndrome (iNS).MethodsA case-control study was performed on iNS patients and healthy from May 2018 to April 2019. Dental caries was assessed by the World Health Organization criteria, developmental defects of enamel by the mDDE index, oral hygiene by the OHI-S and API, and gingival condition by the GI. Oral health behavior was recorded using a standardized questionnaire including tooth brushing, fluoride prevention, dietary habits and utilization of dental care. Additionally, Streptococcus mutans (SM) and Lactobacillus spp. (LB) bacteria in saliva were assessed using the CRT bacteria test. Statistical analysis comparing oral health parameters was carried by Pearson's chi-squared, Fisher's exact, Shapiro-Wilk verified by Student's t or Mann-Whitney U tests.ResultsThe study included 94 participants of both sexes at the age of 4 to 17 years (47 cases and 47 controls) who were treated in Clinic of Pediatric Nephrology or outpatients' dental clinic in Wroclaw, Poland. The iNS patients compared to the controls revealed some lower caries experience (83.0% vs 95.7%) and number of caries affected primary and/or permanent teeth (4.6 ± 3.5 vs 6.0 ± 4.1), a significantly lower number of filled primary and/or permanent teeth (1.1 ± 1.6 vs 3.5 ± 3.0, P < 0.001) and higher incidence of enamel hypoplasia (31.9% vs 4.3%, P < 0.001). The numbers of the iNS patients with high level of SM and LB were similar to the controls. The iNS patients had a higher OHI-S score (1.89 ± 1.59 vs 1.05 ± 1.02, P < 0.010) and a higher GI score (0.7 ± 1.0 vs 0.3 ± 0.6, P = 0.050). Moreover, they less frequently brushed their teeth twice a day (78.8% vs 93.6%, P = 0.026) and more frequently consumed three or more snacks daily (53.2% vs 23.4%, P = 0.002).ConclusionsThe iNS patients despite the poor oral hygiene revealed lower caries experience but smaller number of restored caries-affected teeth, more severe gingivitis and more frequently teeth affected by enamel hypoplasia.

Dataset Information

A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

Publications

A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

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