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Background There seems to be a possible link between nephrotic syndrome (NS) and lymphoproliferative syndrome, but it remains poorly understood. Methods This multicentric and retrospective study focuses on children, who developed idiopathic NS and malignant or benign proliferation between 2000 and 2021. Results Eleven patients were included, with a median age of 4 years. Only one had a steroid-resistant nephrotic syndrome (SRNS). The maintenance therapy before the proliferation was in majority tacrolimus or mycophenolate mofetil (MMF), but three patients did not receive treatments. The proliferation was mainly a Hodgkin's lymphoma (45%) or a lymphoproliferative disease (36%), in a median time after the NS of two years. Viruses were found in seven cases (EBV in five cases and HHV-8 in two). Conclusion The association between proliferative syndrome and idiopathic NS may not be fortuitous, possibly with a common lymphocytic disturbance. Genetic analyses could improve the comprehension of these manifestations in the future. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Clara Cébron [sup.1] [sup.2] , Astrid Godron-Dubrasquet [sup.3] , Nathalie Aladjidi [sup.4] , Gwenaelle Roussey [sup.5] , Olivia Boyer [sup.6] , Marina Avramescu [sup.6] , Veronique Baudouin [sup.7] , [...]

Original citation: J Clin Invest. 2020;130(1):335-344. https://doi.org/10.1172/JCI129937. Citation for this corrigendum: J Clin Invest. 2022;132(11):e161852. https://doi.org/10.1172/JCI161852. The authors recently became aware that the standard errors for the diabetes group were [...]

Background Prospective studies have established the mycophenolate mofetil (MMF) efficiency in childhood idiopathic nephrotic syndrome (INS) but reports on the long-term outcome are lacking. Moreover, the search for factors influencing its efficiency would be useful to define its place among the other treatments. Methods We performed a monocentric retrospective study including 96 children with steroid-dependent INS followed for 4.7 years (median) (IQ 3-6) after the onset of MMF treatment. The characteristics of responder patients (n = 74), as defined by a 50 % decrease of relapse rate and/or a 60 % decrease of steroid dose, and of non-responder patients (n = 22) were compared by univariate analysis and multivariate logistic regression. Results Withdrawal of prednisone was achieved in 48/96 patients after a median duration of 18.1 months (IQ 7.8-30.0) of MMF. Only 26/48 patients did not relapse under MMF alone. After MMF was stopped in these patients, only six remained in remission without any treatment at last follow-up. Responders had a shorter time to remission at the first flare (9.5 vs. 15 days, p = 0.02), a shorter disease duration prior to the onset of MMF (22.2 vs. 94.5 months, p = 0.001), and were younger at the MMF initiation (6.7 vs. 10.1 years, p = 0.02) than non-responder patients. The age of MMF initiation was an independent factor associated with efficiency (OR = 0.80, 95 % CI [0.69, 0.93], p < 0.01). Conclusions MMF is more efficient in young patients treated early in the disease course. Nevertheless, MMF has no remnant effect while nearly all patients relapsed after withdrawal of the drug., Author(s): Laurène Dehoux[sup.1] , Julien Hogan[sup.1] , Claire Dossier[sup.1] , Marc Fila[sup.1] , Olivier Niel[sup.1] , Anne Maisin[sup.1] , Marie Alice Macher[sup.1] , Theresa Kwon[sup.1] , Veronique Baudouin[sup.1] , Georges [...]

Background C3 glomerulopathy (C3G) is characterized by predominant C3 deposits in glomeruli and dysregulation of the alternative pathway of complement. Half of C3G patients have a C3 nephritic factor (C3NeF). C3G incorporated entities with a range of features on microscopy including dense deposit diseases (DDD) and C3 glomerulonephritis (C3GN). The aim of this work was to study children cases of C3G associated with C3NeF. Methods We reviewed 18 cases of C3G with a childhood onset associated with C3NeF without identified mutations in CFH, CFI, and MCP genes. Results Clinical histories started with recurrent hematuria for seven patients, nephrotic syndrome for four, acute post infectious glomerulonephritis for three and acute renal failure for four. Twelve patients had a low C3 at first investigation. Kidney biopsy showed ten C3GN and eight DDD. Twenty-three percent of the patients tested presented elevated sC5b9. Seven patients relapsed 3 to 6 years after the onset. At the end of follow-up, two patients were under dialysis, 11 had a persistent proteinuria, five had none; four patients did not follow any treatment. Steroids were first used in 80% of cases. Conclusions C3NeF associated C3G has a heterogeneous presentation and outcome. Anti-proteinuric agents may control the disease during follow-up, even after nephrotic syndrome at the onset. The efficiency of immunosuppressive therapy remains questionable. Keywords Complement alternative pathway * C3 glomerulonephritis * Dense deposit disease * Membranoproliferative glomerulonephritis * C3 glomerulopathy, Introduction C3 glomerulopathy (C3G) is the term now used for C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), both subtypes resulting from dysregulation of the alternative pathway (AP) of complement [...]

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/[m.sup.2]/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/[m.sup.2] e.o.d (p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/[m.sup.2]/month (p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide. Keywords Idiopathic nephrotic syndrome * Steroid-dependent nephrotic syndrome * Mycophenolate mofetil * Mycophenolic acid pharmacokinetics * Bayesian trial, Introduction Most pediatric patients with idiopathic nephrotic syndrome (INS) respond to steroids, but approximately 60% present long-term steroid dependency [1]. Prolonged and repeated use of high-dose steroids results in serious [...]

In order to determine the long-term effects of cyclophosphamide (CPO) and to identify parameters associated with sustained remission, we retrospectively studied the data from 90 patients with steroid-dependent nephrotic syndrome (SDNS) who received a single course of oral cyclophosphamide (2 mg/kg/day for 10 to 12 weeks). The median follow-up period after CPO was 5.5 years (interquartile range 3.2-8.5). Sustained remission reached the cumulative rate of 57% at 1 year, 42% at 2 years, and 31% at 5 years. For the patients who relapsed, the median threshold dose of prednisone between CPO initiation and first relapse has significantly decreased (22.1 mg/kg/day versus 4.9 mg/kg/day, p < 0.001). No further immunosuppressive agent was required in 60% of all patients. Young age at CPO initiation was associated with a lower rate of sustained remission (p < 0.001). Age at diagnosis of nephrotic syndrome, gender, cumulative dose of CPO (in mg/kg), and level of steroid dependence at CPO initiation did not influence the outcome. The incidence of side effects was low. These findings suggest that despite the wide use of new immunosuppressive agents, a short course of CPO remains an effective second-line therapy in SDNS patients. Optimal efficiency was observed in children over 7.5 years., Author(s): Sonia Azib [sup.1] , Marie Alice Macher [sup.1] , Theresa Kwon [sup.1] , Agnes Dechartres [sup.1] , Corinne Alberti [sup.2] , Chantal Loirat [sup.1] , Georges Deschênes [sup.1] , [...]

The development of membranoproliferative glomerulonephritis (MPGN) is associated with uncontrolled activation of the complement alternative pathway. This dysregulation is related either to C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase, or to homozygous loss-of-function mutation of the complement regulatory protein factor H. Heterozygous mutations in the genes coding for factor H, or for the other alternative pathway inhibitory proteins factor I and membrane cofactor protein, have recently been identified in a small number of patients with MPGN with exclusive C3 deposits. We report three hypocomplementemic children with dense deposit disease (n =1) or immune-complex-mediated MPGN type I (n=2), associated with both C3NeF activity and heterozygous mutation of factor H or factor I. These observations highlight the possible combination of genetic and acquired defect in complement control in various subtypes of MPGN, a finding that may influence the treatment strategy in some patients. Keywords Membranoproliferative glomerulonephritis type I * Dense deposit disease * Complement alternative pathway * C3 nephritic factor * Factor H. Factor I, Introduction Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare disease accounting for 3-5% of primary nephrotic syndrome in childhood [1, 2]. This entity refers to a characteristic histological pattern defined by [...]

Although most patients with idiopathic nephrotic syndrome (NS) respond to steroid treatment, development of steroid dependency may require a long-term multidrug therapy including steroid and calcineurin inhibitor. Rituximab was shown to allow a reduction of the doses of steroid and immunosuppressive drugs in those patients. In the present series, 22 patients with steroid-sensitive, but steroid-dependent nephrotic syndrome were treated with rituximab. Rituximab reduced B cell count down to an undetectable level in all patients. A second treatment was necessary in 18 patients in order to maintain B cell depletion for up to 18 months. B cell depletion lasted 4.9 to 26 months (mean 17.2 months). At last follow-up, 9 patients were in remission without oral steroid or calcineurin inhibitor, although B cell count had recovered for 2.9 to 17 months (mean 9.5 months). A remission under ongoing B cell depletion was observed in 10 other patients in the absence of oral steroid or calcineurin inhibitor. Rituximab failed in 2 patients and 1 refused any additional treatment, despite B cell recovery and relapse. Toxicity of rituximab was limited to reversible cytokine shock in 2 patients and reversible neutropenia in 1 patient. No severe infection was observed. Keywords Rituximab * Idiopathic nephrotic syndrome * CD19 * B cell depletion * Steroid dependency. Immunosuppressive treatment, Introduction Idiopathic nephrotic syndrome is the most frequent glomerular disease during childhood. Most patients respond to steroid treatment, but a significant number develop steroid dependency. Although many immunosuppressive agents proved [...]

African histoplasmosis caused by Histoplasma capsulatum var. duboisfi is an invasive fungal infection endemic in central and west Africa. Most of its ecology and pathogenesis remain unknown. H. capsulatum var. [...]

Abstract The occurrence of membranous nephropathy in pediatric series of systemic lupus erythematosus has been reported only rarely, probably due to a very low frequency. One hundred fifty-four children who [...]

Byline: D. Simon (1), Myriam Rosilio (2), Anne Maisin (3), Michel Remesy (4), Veronique Baudouin (3), Chantal Loirat (3), Paul Czernichow (1) Keywords: Key wordsaChronic renal failure; Renal transplantation; Growth; Puberty; Recombinant human growth hormone therapy; Steroid therapy; Final height Abstract: Sixteen prepubertal patients with chronic renal failure (CRF) were given daily recombinant human growth hormone (rhGH) treatment (1.2 IU/kg per week) for 2.6+-1.6 years until kidney transplant. Therapy was then discontinued and the patients followed for a further 3.5+-1.4 years. During treatment, mean height increased from --3.0+-0.9 standard deviation score (SDS) to --1.9+-1.4 SDS (P&lt 0.001) at the time of transplantation, corresponding to a mean height gain of +1.2+-0.9 SDS. After discontinuation of rhGH therapy, prepubertal children continued a partial catch-up growth with a height gain of +0.5+-0.8 SDS for the follow-up period. Conversely, negative changes of height were observed in pubertal transplanted children: --0.5+-0.4 SDS in patients grafted at early stages of puberty (P2--P3) and --0.15+-0.9 SDS in patients grafted at late stages of puberty (P4--P5). These data confirmed the benefit of rhGH therapy in CRF patients. Nevertheless, only early initiation of rhGH treatment led some of these patients to their target height at transplantation, thus preserving their potential growth. Reinitiation of rhGH therapy after transplantation should be considered in order to complete catch-up growth to target height in prepubertal children. Author Affiliation: (1) Pediatric Endocrinology and Diabetology Unit, Robert Debre Hospital, 48 Boulevard Serurier, F-15019 Paris, France e-mail: dominique.simon@rdb.ap-hop-paris.fr Tel.: +33-1-40032000 (extension 3386), Fax: +33-1-40032429, FR (2) Lilly Laboratories, Saint-Cloud, France, FR (3) Pediatric Nephrology Unit, Robert Debre Hospital, Paris, France, FR (4) Pediatric Nephrology Unit, Purpan Hospital, Toulouse, France, FR Article note: Received: 23 July 1998 / Revised: 8 December 1998 / Accepted: 13 December 1998

Background: Children are recognised as at lower risk of severe COVID-19 compared with adults, but the impact of immunosuppression is yet to be determined. This study aims to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess disease severity.Methods: Cross-sectional study hosted by the European Rare Kidney Disease Reference Network and supported by the European, Asian and International paediatric nephrology societies. Anonymised data were submitted online for any child (age <20 years) with COVID-19 taking immunosuppressive medication for a kidney condition. Study recruited for 16 weeks from 15 March 2020 to 05 July 2020. The primary outcome was severity of COVID-19.Results: 113 children were reported in this study from 30 different countries. Median age: 13 years (49% male). Main underlying reasons for immunosuppressive therapy: kidney transplant (47%), nephrotic syndrome (27%), systemic lupus erythematosus (10%). Immunosuppressive medications used include: glucocorticoids (76%), mycophenolate mofetil (MMF) (54%), tacrolimus/ciclosporine A (58%), rituximab/ofatumumab (11%). 78% required no respiratory support during COVID-19 illness, 5% required bi-level positive airway pressure or ventilation. Four children died; all deaths reported were from low-income countries with associated comorbidities. There was no significant difference in severity of COVID-19 based on gender, dialysis status, underlying kidney condition, and type or number of immunosuppressive medications.Conclusions: This global study shows most children with a kidney disease taking immunosuppressive medication have mild disease with SARS-CoV-2 infection. We therefore suggest that children on immunosuppressive therapy should not be more strictly isolated than children who are not on immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. Methods We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. Results The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9–52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. Conclusions Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients. [ABSTRACT FROM AUTHOR]

BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB). [ABSTRACT FROM AUTHOR]