X-linked transient antenatal Bartter syndrome related to MAGED2 gene: enriching the phenotypic description and pathophysiologic investigation.

PURPOSE: Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women. METHODS: We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples. RESULTS: Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%) and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women. CONCLUSION: This work enriches the phenotypic and genetic description of this recently described disease, and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.

Juvenile neuropsychiatric systemic lupus erythematosus: A specific clinical phenotype and proposal of a probability score.

OBJECTIVE: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic auto-immune disease involving several organs. Neuropsychiatric (NP) SLE (NPSLE) is frequent in j-SLE and associated with increased morbidity/mortality. Although NPSLE classification criteria exist, attributing NP features to j-SLE remains a major challenge. The study objective is to thoroughly describe j-NPSLE patients and assist in their diagnosis. METHODS: This is a 4-year retrospective monocentric study of j-SLE patients. NP events were attributed to j-SLE using standardised diagnostic criteria and multidisciplinary paediatric clinical expertise. Clinical features, brain magnetic resonance imaging (MRI)s and samples analysis including cerebrospinal fluid were assessed. A risk of j-NPSLE score was developed based on multivariable logistic regression analysis. RESULTS: Of 39 patients included, 44% were identified as having j-NPSLE. J-NPSLE diagnosis was established at the onset of j-SLE in 59% of patients. In addition to frequent kidney involvement (76%) and chilblains (65%), all j-NPSLE patients displayed psychiatric features: cognitive symptoms (82%), hallucinations (76%), depressed mood (35%), acute confused state (18%) and catatonia (12%). Neurological involvement was often mild and nonspecific, with headache (53%) in about half of the patients. The main features reported on brain MRI were nonspecific T2/FLAIR white matter hyperintensities (65%), and cerebral atrophy (88%). Upon immunosuppressive treatment, clinical improvement of NP features was observed in all j-NPSLE patients. The score developed to attribute j-NPSLE probability, guide further investigations and appropriate treatments is based on hallucinations, memory, sleep and renal involvement (Sensitivity: 0.95 Specificity: 0.85). Cerebrospinal fluid (CSF) neopterin assessment increases the score sensitivity and specificity. CONCLUSION: Physicians should carefully and systematically assess the presence of NP features at diagnosis and early stages of j-SLE. For j-NPSLE patients with predominant psychiatric features, a multidisciplinary collaboration, including psychiatrists, is essential for the diagnosis, management and follow-up.

IgG-immunoadsorptions and eculizumab combination in STEC-hemolytic and uremic syndrome pediatric patients with neurological involvement.

BACKGROUND: Neurological complications pose a significant threat in pediatric hemolytic and uremic syndrome (HUS) resulting from infections with Shiga toxin-producing Escherichia coli (STEC), with no established treatment. The involvement of complement activation in the pathogenesis of STEC-HUS is acknowledged, and eculizumab (ECZ), a terminal complement blocker, has been documented in several pediatric series with inconsistent results. Antibody-mediated mechanisms have also been suggested, with IgG-immunoadsorption (IgIA) showing promise in adults with neurological complications. We aimed to assess the benefit of combining IgIA with ECZ in pediatric patients with neurological STEC-HUS compared to patients treated with ECZ alone or supportive care. METHODS: Multicenter retrospective study conducted on pediatric patients (< 18 years) with neurological STEC-HUS treated with IgIA + ECZ or ECZ alone from 2010 to 2020 in France. A historical cohort treated with supportive care served as controls. Primary outcome included survival and neurological evaluation at 1-year follow-up (dichotomized as normal vs. abnormal). RESULTS: A total of 42 children were included: 18 treated with IgIA + ECZ, 24 with ECZ alone, and 27 with supportive care. Although there was no significant difference in survival between groups, three deaths occurred in the control group in the acute phase, while none was reported in both the IgIA + ECZ and ECZ alone groups, despite presenting with more severe neurological symptoms for IgIA + ECZ patients. No significant association was found between treatment group and 1-year neurological evaluation after adjustment for age, sex, and initial neurological presentation. CONCLUSIONS: Systematic association of IgIA + ECZ is not supported for all neurological STEC-HUS pediatric patients; potential rescue therapy for severe cases warrants consideration.

Anti-CFH-associated hemolytic uremic syndrome: do we still need plasma exchange?

BACKGROUND: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. METHODS: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. RESULTS: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients. CONCLUSIONS: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.

Biallelic NPR1 loss of function variants are responsible for neonatal systemic hypertension.

BACKGROUND: Early-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger children and neonates. We investigated the genetic bases of early-onset isolated systemic hypertension. METHODS: Whole-exome sequencing (WES) was followed by variant filtering and Sanger sequencing for validation and familial segregation of selected variants in a large consanguineous family. mRNA expression was performed to evaluate the impact of the predicted pathogenic variant on gene expression. WES or Sanger sequencing was performed in additional unrelated affected individuals. RESULTS: In one consanguineous family with four children presenting with isolated neonatal-onset systemic hypertension, we identified homozygous stop-gain variant in the NPR1 gene (NM_000906.4:c.1159C>T (p.Arg387Ter)) in the affected individuals. This variant leads to a dramatic reduction of NPR1 RNA levels. NPR1 gene analysis of additional families allowed the identification of another family with two affected children carrying homozygous frameshift variant in NPR1 (NM_000906.4:c.175del (p.Val59TrpfsTer8)). CONCLUSION: We show for the first time that biallelic loss of function of NPR1 is responsible for isolated neonatal-onset systemic hypertension in humans, which represents a new autosomal recessive genetic cause of infantile systemic hypertension or cardiogenic shock. This is consistent with studies reporting early-onset systemic hypertension and sudden death in Npr1-deficient mice. NPR1 gene analysis should be therefore investigated in infants with early-onset systemic hypertension with or without cardiogenic shock of unknown origin.

Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial.

SIGNIFICANCE STATEMENT: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) is a serious condition, characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis. So far, no specific treatment has been proven efficient in STEC-HUS. The use of eculizumab, a monoclonal antibody inhibiting terminal complement complex, has demonstrated remarkable success in atypical hemolytic uremic syndrome, but its use in uncontrolled studies to treat STEC-HUS has yielded inconsistent results. In this Phase 3 randomized, placebo-controlled trial in 100 pediatric patients with STEC-HUS, the findings did not show efficacy of eculizumab during the acute phase of the disease. However, the results indicated a reduction of renal sequelae in eculizumab-treated patients at 1-year follow-up. Larger prospective studies would be needed to further explore eculizumab as a potential treatment. BACKGROUND: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT. Furthermore, at least 30% of survivors experience kidney sequelae. Recently, activation of the complement alternative pathway has been postulated as a factor in STEC-HUS pathophysiology, leading to compassionate use of eculizumab, a monoclonal antibody inhibiting the terminal complement complex, in affected patients. Given the lack of therapy for STEC-HUS, a controlled study of eculizumab efficacy in treating this condition is a priority. METHODS: We conducted a Phase 3 randomized trial of eculizumab in children with STEC-HUS. Patients were randomly assigned in a 1:1 ratio to receive either eculizumab or placebo during 4 weeks. Follow-up lasted for 1 year. The primary end point was RRT duration <48 hours after randomization. Secondary endpoints included hematologic and extrarenal involvement. RESULTS: Baseline characteristics were similar among the 100 patients who underwent randomization. The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF. The two groups also exhibited similar hematologic evolution and extrarenal manifestations of STEC-HUS. The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04). No safety concern was reported. CONCLUSIONS: In pediatric patients with STEC-HUS, eculizumab treatment does not appear to be associated with improved renal outcome during acute phase of the disease but may reduce long-term kidney sequelae. CLINICAL TRIALS REGISTRATIONS: EUDRACT (2014-001169-28) ClinicalTrials.gov ( NCT02205541 ).

Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers.

INTRODUCTION: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. OBJECTIVES: To identify central nervous system (CNS) disease biomarkers of j-NPSLE. METHODS: A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. RESULTS: Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p < 0.0001, n = 23 paired samples). CONCLUSION: CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.

Benefits of BNP/NT-proBNP serum level evaluation for dry weight adjustment in pediatric hemodialysis patients.

BACKGROUND: Dry weight (DW) adjustment in children on hemodialysis (HD) can be challenging. It relies on clinical evaluation and additional supports. Our aim was to study the benefits of cardiac biomarker assessment, in addition to the more commonly used technique, bioimpedance spectroscopy (BIS), and clinical signs for DW prescription in pediatric HD patients. METHOD: Observational study including 41 children on HD in three pediatric HD centers in the Paris region. During one session, BIS was performed before the session and serum levels of BNP and NT-proBNP were analyzed before and after the session. RESULTS: Median pre-dialysis level of BNP was 87 ng/L [24-192] and NT-proBNP 968 ng/L [442-4828]. Cardiac biomarker levels showed positive correlation with the BIS hydration status evaluation (p = 0.004). The most appropriate cutoff for pre-dialysis BNP to detect significant overhydration (OH) was 165 ng/L (sensitivity 0.67, specificity 0.84). Based on the BIS evaluation, only 32% of patients with high blood pressure (BP) had OH, whereas in the normal BP group, 33% had significant OH. CONCLUSIONS: DW prescription for children on HD should not only rely on clinical evaluation, particularly BP, but should also include additional helpful parameters. BIS is well-validated in children, but it has limitations in non-cooperative patients, and its cost can limit its use in some settings. Cardiac biomarkers, especially BNP, were well-correlated to hydration status evaluated by BIS, and thus could add valuable information for individual patient management and DW assessment. A higher resolution version of the Graphical abstract is available as Supplementary information.

Renal vein thrombosis in neonates: a case series of diagnosis, treatment and childhood kidney function follow-up.

BACKGROUND: Neonatal renal vein thrombosis (NRVT) is a rare condition with little data available. METHODS: We retrospectively analyzed newborns diagnosed with NRVT admitted to 3 pediatric nephrology units in Paris from 2005 to 2020. RESULTS: Twenty-seven patients were analyzed (male = 59%). The median age at diagnosis was 2.5 days (1 - 4.5). Diagnosis was suspected based on at least one of the three cardinal signs of renal vein thrombosis in 93%: flank mass (67%), hematuria (67%) and thrombocytopenia (70%). In all patients, diagnosis was confirmed by ultrasound. All patients had at least one known perinatal risk factor. A prothrombotic risk factor was found in 13 patients (48%). NRVT was unilateral in 70%, involving the left renal vein in 58%. Among 25 treated patients, 19 (76%) received low molecular weight heparin (LMWH) as initial therapy, 2 (8%) received unfractionated heparin and 4 (16%) received fibrinolysis. Median duration of treatment was 8 weeks (4 - 12). Bleeding occurred significantly more often with fibrinolysis than with LMWH/supportive therapy (3 of 4: 75% vs 0 of 4: 0%, p = 0.05). Clot resolution in patients treated with fibrinolysis did not differ significantly from those treated with LMWH/supportive therapy. After a median follow-up of 5.7 years (3 years - 9.9 years), pathological kidney features were observed in 73% of the patients (19 of 26), kidney atrophy in 18 (69%), hypertension in 2 (8%), chronic kidney disease (CKD) in 1 (4%) and proteinuria in 2 (8%). CONCLUSIONS: NRVT remains a challenging condition, which still requires further study because of its associated morbidity. A higher resolution version of the Graphical abstract is available as Supplementary information.

Specific immune biomarker monitoring in two children with severe IgA nephropathy and successful therapy with immunoadsorption in a rapidly progressive case.

BACKGROUND: Childhood IgA nephropathy (cIgAN) is one of the most common primary glomerulonephritides with the potential to evolve to kidney failure. IgAN is an autoimmune disease involving 3 key factors: galactose-deficient IgA1 (Gd-IgA1), anti-IgA1 autoantibodies, and soluble (s)CD89 IgA Fc receptor. These molecules and immune complexes have been described recently as potential biomarkers of disease progression in childhood IgAN but their evolution in time under immunosuppressive treatment remains unknown. METHODS: We performed a prospective study of two proliferative cIgAN patients by sequentially biomonitoring immune IgA complexes (sCD89-IgA, IgG-IgA), sCD89, and Gd-IgA1 and correlating them with clinical and histological outcome after treatment. RESULTS: After patient 1's treatment, a decrease in sCD89-IgA, IgG-IgA, and free sCD89 was linked to a decrease in proteinuria whereas eGFR (estimated glomerular filtration rate) and Gd-IgA1 levels remained stable. Patient 1 received tacrolimus and monthly intramuscular steroid injections of Kenacort for 10 months. At the end, a relapse induced an increase in proteinuria consistent with an increase of the 3 biomarkers. Patient 2 displayed rapidly progressive IgAN with crescents in more than 90% of glomeruli and received intense immunosuppression treatment associated with the immunoadsorption (IA) approach. During IA, proteinuria decreased rapidly, as well as levels of CD89-IgA, IgG-IgA, sCD89, and Gd-IgA1 biomarkers. After discontinuation of IA, proteinuria increased as well as IgG-IgA complexes whereas sCD89-IgA and sCD89 remained low. Further re-intensification of IA and addition of cyclophosphamide improved proteinuria again with reduced IgG-IgA. A second biopsy was performed showing a reduction of extracapillary proliferation to 6% of glomeruli and only 9% glomerulsoclerosis. CONCLUSIONS: In conclusion, sequential biomonitoring of Gd-IgA1, IgA-immune complexes, and sCD89 in cIgAN was found to be valuable, by correlating with clinical features and glomerular proliferative lesions in cIgAN. These biomarkers could represent useful tools to evaluate kidney injury without repeat kidney biopsies.

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.

Procalcitonin serum levels in stage 5 chronic kidney disease children on hemodialysis.

BACKGROUND: Infections are responsible for morbidity and mortality in children on hemodialysis (HD). Procalcitonin (PCT) is rarely used in this population, even though it is an efficient biomarker of infection and sepsis. Our aim was to study PCT baseline level in uninfected children with stage 5 chronic kidney disease (CKD 5) on HD, and determine how to use it in this population. METHODS: Prospective observational study including 40 uninfected children on classical HD or hemodiafiltration (HDF) in three pediatric HD centers in the Paris region. PCT was monitored before and after three consecutive sessions within 1 week. RESULTS: Median pre-dialysis PCT was 0.60 ng/mL [0.36-1.15], median post-dialysis PCT was 0.23 ng/mL [0.10-0.47], PCT reduction rate was 59.8% [37.5-75.8]. Seventy percent of pre-dialysis PCT were <1 ng/mL. Anuric patients had higher pre-dialysis PCT than those with residual urine output (0.70 [0.42-1.30] vs. 0.48 [0.30-0.93] ng/mL, p=0.01). HDF was more efficient than HD to clear PCT during sessions (reduction rate 75% [67-80] vs. 37 [31-50]), p<0.001). CONCLUSION: PCT levels in pediatric HD patients without infection are higher than normal, but this increase is relatively moderate compared to massive increases of PCT in children with bacterial infections on HD. If PCT is measured after dialysis sessions, the specific technique-dependent reduction rates should be taken into consideration. Moderately increased PCT levels around 2 ng/ml should be interpreted with caution; however, higher PCT serum levels can be used to motivate rapid start of antibiotic treatment in pediatric HD patients.

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.

Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.

OBJECTIVES: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). METHODS: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. RESULTS: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. CONCLUSION: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

Asymptomatic bacteriuria in pediatric kidney transplant recipients: to treat or not to treat? A retrospective study.

BACKGROUND: Urinary tract infections (UTI) are common infectious complications in kidney transplant recipients (KTR); asymptomatic bacteriuria (AB) is also frequent. It is unclear whether treatment of AB reduces subsequent UTI in KTR; no guideline is available in pediatric KTR. In this retrospective study, we analyzed the incidence of AB in pediatric KTR and the impact of screening and treating AB on the onset of subsequent UTI. METHODS: Thirty-seven pediatric patients were included. Inclusion criteria were the occurrence of one or more episodes of AB between 2 and 24 months post-renal transplantation. Primary outcome was the cumulative incidence of acute pyelonephritis (APN) or lower urinary tract infections (LUTI) occurring between 2 and 24 months post-renal transplantation. RESULTS: Thirty-seven patients presented 171 AB episodes. One hundred sixty-four AB episodes were untreated (95.9%); among them, 150 episodes (91.5%) were not followed by a clinical infection. Ten episodes (6.1%) led to APN, and 4 (2.4%) to LUTI. There were 53 episodes of APN: 10 (18.9%) after untreated AB and 43 (81.1%) de novo. There were 11 episodes of LUTI: 4 (36.4%) after untreated AB and 7 (63.6%) de novo. Multi-drug resistant bacteria were present in 27% of the patients and in 20% of patients with pre-existing uropathy. CONCLUSIONS: Our results are not in favor of systematic treatment of AB in pediatric KTR. Notably, limitation of antibiotic treatment is an urgent and important health issue in this population, in order to reduce multi-drug resistant bacteria emergence.

Ultrasound dilution and thermodilution versus color Doppler ultrasound for arteriovenous fistula assessment in children on hemodialysis.

BACKGROUND: This study is aimed at comparing ultrasound dilution (UD) and thermodilution (TD) with color Doppler ultrasound (CDU) for arteriovenous fistula (AVF) assessment in children on hemodialysis (HD). MATERIAL AND METHODS: All patients were dialysed with the Fresenius 5008 HD machine. UD was performed using the Transonic device. The two methods were compared with CDU performed on a non-HD day. AVF flow rate was expressed as ml/min/1.73 m2. RESULTS: Sixteen measurements of AVF flow rate and recirculation with UD and TD were compared with CDU in 16 patients with a median weight of 39 kg. Both UD and TD overestimated AVF flow rate when compared with CDU (+437 (95% CI + 200, + 674) and + 476 (95% CI + 80, + 871) ml/min/1.73 m2 for UD and TD, respectively). CDU flow rate was significantly correlated to UD flow rate (r2 = 0.761, p < 0.001), but not to TD flow rate (r2 = 0.164, p = 0.120). Although recirculation in all AVF was estimated to be 0% and < 15% with UD and TD, respectively, 7 significant stenoses were diagnosed by CDU. AVF with stenosis had lower flow rates when measured by CDU, UD or TD, but only CDU measurements reached statistical significance (p = 0.008, p = 0.142 and p = 0.174, respectively). CONCLUSION: UD and TD overestimate AVF flow rate when compared with CDU, which is the most reliable non-invasive method for screening vascular access for stenosis. UD seems more accurate than TD for AVF flow rate assessment. Recirculation via UD or TD should not be used for early screening of AVF stenosis in children on HD.

Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome.

BACKGROUND: Several studies have demonstrated that rituximab (RTX) improves relapse-free survival in patients with steroid-dependent nephrotic syndrome (SDNS). However, these studies used various RTX regimens and there are few data comparing these regimens in children with SDNS. In this retrospective study, we assessed the effect of three different initial RTX regimens on both time to B cell reconstitution and to first relapse. METHODS: Sixty-one SDNS patients receiving a first course of RTX were included. Group 1 received one injection of 100 mg/m2, group 2 received one injection of 375 mg/m2, and group 3 received two injections of 375 mg/m2 at day 0 and day 7. Time to B cell reconstitution and time to first relapse and respective risk factors were studied. RESULTS: Median time to B cell reconstitution was 2.5 [1.8-3.5], 5.0 [3.9-6.0], and 6.6 [4.6-7.8] months in groups 1, 2, and 3, respectively. RTX regimen was associated with time to B cell reconstitution (HRs group 2 vs. 3, 4.07 [1.96-8.48]; group 1 vs. 3, 11.13 [4.04-30.67]). One-year relapse-free survival was 50% [58-77], 59% [42-76], and 72% [46-87] in groups 1, 2, and 3, respectively. RTX regimen was associated with risk of relapse (HRs group 2 vs. 3, 1.55 [0.51-4.65]; group 1 vs. 3, 4.98 [1.15-21.60]). CONCLUSIONS: The initial dose of rituximab impacts time to B cell reconstitution and the probability of relapse. Risk of relapse is also associated with patient characteristics, suggesting that RTX regimen could be modified for each patient to balance efficacy, cost, and side effects.

Effect of nonsteroidal anti-inflammatory drugs in children with Bartter syndrome.

BACKGROUND: Bartter syndrome (BS) is a salt-wasting tubulopathy with induced expression of cyclooxygenase-2 in the macula densa, leading to increased prostaglandin production and hyperreninemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in BS; however, there is limited information on the impact of NSAIDs at treatment initiation or the potential utility of plasma renin level to guide therapy in patients with BS. METHODS: We included 19 patients with BS treated with NSAIDs between 1994 and 2016. We assessed serum levels of renin, aldosterone, electrolytes, calcium, phosphorus, vitamin D, and intact parathyroid hormone (iPTH) before and after treatment initiation. We also recorded modifications in sodium and potassium supplements and changes in urine calcium. RESULTS: Median age at diagnosis was 0.9 months [IQR 0-6.9]. Seven patients had BS types 1 or 2, 12 had BS type 3 and two had no mutation identified. There was a trend towards a decrease in sodium chloride supplementation after initiation of NSAIDs. When defining response to treatment based on the normalization of plasma renin level, responders had a greater reduction in their electrolytes supplementation. NSAIDs treatment was associated with a reduction in urine calcium. Before treatment, half of the patients had elevated iPTH, but iPTH normalized following initiation of NSAIDs in all but one patient. CONCLUSIONS: This study confirms that NSAIDs reduce urine wasting of sodium and calcium in patients with BS. Monitoring serum renin levels may be useful to identify the lowest effective dose of NSAIDs that optimizes reduction of urine electrolyte losses.

Remission of proteinuria in multidrug-resistant idiopathic nephrotic syndrome following immunoglobulin immunoadsorption.

AIM: Complete or partial resistance to prednisone and calcineurin inhibitors in children with idiopathic nephrotic syndrome often leads to end-stage renal disease. The aim of the study was to report the outcome of patients with multidrug-resistant nephrotic syndrome treated with an association of immunoglobulin immunoadsorption, intravenous immunoglobulins and B-cell depletion. METHODS: At treatment initiation, patients received ten sessions of immunoglobulin immunoadsorption and intravenous immunoglobulins in two weeks followed by one rituximab in case of remission. RESULTS: A remission of proteinuria was obtained in nine out of 14 patients at the end of the initial phase and in two additional patients after an extended period. The remission was stable in three patients and after additional IgIA and heavy immunosuppression in six. Two patients that initially responded relapsed after IgIA withdrawal and remained with an uncontrolled disease at last follow-up. Three patients did not respond to the treatment including two who were found to have a genetic podocytopathy. CONCLUSION: Patients with multidrug-resistant idiopathic nephrotic syndrome can be successfully led into remission by IgIA prior to reaching end-stage renal disease. However, IgIA does not suppress the need for heavy additional immunosuppression to control INS in most cases.

Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric kidney transplantation: a multicentre French cohort.

Background: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (KTx) in children. This can lead to delayed graft loss. As the management of children with recurrent FSGS is not well established, apheresis strategies could be a cornerstone to control the disease. Immunoadsorption (IA) is a recent apheresis therapy. There have been few studies examining IA in this setting. We report the results of IA for management of recurrent FSGS after KTx in children in France. Methods: We included all children treated with IA for early FSGS recurrence after KTx between January 2011 and June 2014 in France. We excluded genetic forms of FSGS. Patients' characteristics and technical data on IA were retrospectively collected. Recurrence was defined as nephrotic proteinuria during the post-transplantation period. Partial and complete remissions were defined when urine protein:creatinine ratios were less than 0.2 and 0.05 g/mmol, respectively. Results: Twelve patients, from six paediatric KTx units, presenting with FSGS recurrence between 0 and 21 days after KTx were treated with IA. Ten of 12 children were responders: 2 achieved partial remission and 8 complete remission. The decrease of proteinuria rapidly occurred within the first 10 sessions after initiating IA. After 3 months of IA, two patients maintained remission without IA and eight became IA dependent. No severe side effects were reported. Conclusions: Our study reports on the efficacy of IA in the recurrence of FSGS after KTx in children. Further prospective controlled studies are required to confirm these results and to optimize the management of FSGS recurrence after paediatric KTx.