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.

Obinutuzumab in Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome in Children.

BACKGROUND: B-cell depletion with rituximab induces sustained remission in children with steroid-dependent or frequently relapsing nephrotic syndrome. However, most patients relapse after B-cell recovery, and some patients do not achieve B-cell depletion. Obinutuzumab is a second-generation anti-CD20 antibody designed to overcome such situations in B-cell malignancies and was recently reported to be safe and effective in other autoimmune diseases affecting the kidneys. METHODS: We retrospectively report 41 children with steroid-dependent or frequently relapsing nephrotic syndrome treated with a single low-dose infusion of obinutuzumab at Robert-Debre Hospital between April 2018 and December 2020. Participants were treated because of rituximab resistance or relapse after rituximab and received a single infusion of 300 mg/1.73 m 2 obinutuzumab with cessation of oral immunosuppressors within 2 months. RESULTS: B-cell depletion was achieved in all participants and lasted a median of 8.3 months (interquartile range, 6.4-11.1), a duration exceeding that for last rituximab treatment. At 12 and 24 months, 92% (38/41) and 68% (28/41) of patients, respectively, were in sustained remission. Mild infusion reactions occurred in five participants (12%) and neutropenia in nine (21%). No significant decrease in IgG level was reported during treatment, and whereas IgM levels decreased in 34 patients (83%), they were normal at last follow-up in 32 (78%). CONCLUSIONS: These results identified low-dose obinituzumab as a promising treatment option in children with steroid-dependent or frequently relapsing nephrotic syndrome, including those resistant to rituximab. The tolerance profile of obinutuzumab was similar to that of rituximab, but hemogram and immunoglobulin levels should be monitored.

Rare Variants in Complement Gene in C3 Glomerulopathy and Immunoglobulin-Mediated Membranoproliferative GN.

BACKGROUND: C3 glomerulopathy and idiopathic immunoglobulin-mediated membranoproliferative GN (Ig-MPGN) are rare complement-mediated kidney diseases. Inherited forms of C3 glomerulopathy/Ig-MPGN are rarely described. METHODS: Three hundred ninety-eight patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102) from a national registry were screened for three complement genes: factor H ( CFH ), factor I ( CFI ), and C3 . Patients with rare variant (minor allele frequency <0.1%) were included. Epidemiologic, clinical, and immunologic data at diagnosis and kidney outcomes of patients were retrospectively collected. RESULTS: Fifty-three different rare variants, including 30 (57%), 13 (24%), and ten (19%) in CFH , CFI , and C3 variants, were identified in 66/398 (17%) patients. Thirty-eight (72%) variants were classified as pathogenic, including 20/30 (66%) and 11/13 (84%) variants in CFH and CFI , respectively, impairing synthesis of factor H or factor I regulators. Fifteen of 53 (27%) variants were of unknown significance. At diagnosis, 69% of patients were adult (median age of 31 years). With the exception of biologic stigma of thrombotic microangiopathy, which was more frequent in patients with CFI variants (5/14 [36%] versus 1/37 [3%] and 0% in the CFH group and C3 group, respectively, P < 0.001), the clinical and histologic features were similar among the three variants groups. The kidney outcome was poor regardless of the age at onset and treatment received. Sixty-five percent (43/66) of patients with rare variant reach kidney failure after a median delay of 41 (19-104) months, compared with 28% (55/195) after a median delay of 34 (12-143) months in the nonvariant group. Among 36 patients who received a kidney transplant, 2-year recurrence was frequent, occurring in 39% (12/31), without difference between variant groups, and led to graft failure in three cases. CONCLUSIONS: In our cohort, 17% of C3 glomerulopathy/Ig-MPGN cases were associated with rare variants in the CFH , CFI , or C3 genes. In most cases, a quantitative deficiency in factor H or factor I was identified. The presence of a rare variant was associated with poor kidney survival. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_08_CJN0000000000000252.mp3.

Optimizing COVID-19 Vaccination Strategy in Pediatric Kidney Transplant Recipients: Humoral and Cellular Response to SARS-CoV-2 mRNA Vaccination.

In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865 BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.

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.

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.

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.

De novo NUF2 variant in a novel inherited bone marrow failure syndrome including microcephaly and renal hypoplasia.

In a patient with severe microcephaly, congenital bone marrow failure, growth retardation, and renal hypoplasia, we identified a likely pathogenic variant in NUF2 that impairs the cell's ability to properly complete mitosis. Interestingly, these clinical features as well as the observed cellular alterations are highly reminiscent of what is reported in Fanconi Anaemia supporting a unifying causal role of the variant in the disease. This case provides the first evidence that a kinetochore defect, previously associated with microcephaly, can be responsible for an inherited bone marrow failure syndrome, highlighting the unique pathological link between neurogenesis and haematopoiesis.

Results from a nationwide retrospective cohort measure the impact of C3 and soluble C5b-9 levels on kidney outcomes in C3 glomerulopathy.

C3 glomerulopathy (C3G) is a rare complement-mediated disease. Specific treatments are not yet available and factors predictive of kidney survival such as age, kidney function and proteinuria are not specific to C3G. The prognostic value of biomarkers of complement activation, which are pathognomonic of the diseases, remains unknown. In a large cohort of 165 patients from the French National registry, we retrospectively assess the prognostic value of C3, soluble C5b-9 (sC5b-9), C3 nephritic factor, and rare disease-predicting variants in complement genes in predicting clinical outcome of patients. By multivariate analysis age (adult onset), reduced kidney function (defined by estimated glomerular filtration rate under 60ml/min) and presence of rare disease-predicting variants in complement genes predicted risk of progression to kidney failure. Moreover, by multivariate analysis, normal C3/high sC5b-9 levels or low C3/normal sC5b-9 levels remained independently associated with a worse kidney prognosis, with the relative risk 3.7- and 8-times higher, respectively. Subgroup analysis indicated that the complement biomarker profiles independently correlated to kidney prognosis in patients with adult but not pediatric onset. In this subgroup, we showed that profiles of biomarkers C3 and/or sC5b-9 correlated with intra glomerular inflammation and may explain kidney outcomes. In children, only the presence of rare disease-predicting variants correlated with kidney survival. Thus, in an adult population, we propose a three-point C3G prognostic score based on biomarker profiles at risk, estimated glomerular filtration rate at presentation and genetic findings, which may help stratify adult patients into subgroups that require close monitoring and more aggressive therapy.

Pharmacokinetics of mycophenolic acid and external evaluation of two limited sampling strategies of drug exposure in patients with juvenile systematic lupus erythematosus.

INTRODUCTION: Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC0-12 h using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance. METHODS: Pharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC-UV). Individual AUC0-12 h at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults. RESULTS: We received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC0-12 h. The external validation MPA AUC0-12 h was conducted by selecting the concentration-time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: - 0.8 mg h/L), (2) ADAPT resulted in a bias of 6.7 mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively. CONCLUSION: According to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC0-12 h in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC0-12 h between 30 and 45 mg h/L is proposed in jSLE but this requires additional validation.

Prenatal bone abnormalities in three cases of familial hypocalciuric hypercalcemia.

INTRODUCTION: Prenatal diagnosis of bone and mineralization anomalies is associated with a wide range of etiologies and prognoses. The improvement of antenatal ultrasound combined with the development of molecular diagnosis in genetics has transformed antenatal medicine into a challenging discipline. Of the various known causes of bone abnormalities and hypomineralization, calcium and phosphate metabolism disorders are exceptional. An accurate diagnosis is crucial for providing appropriate genetic counseling and medical follow-up after birth. CASE: We report on three siblings with severe bone abnormalities diagnosed during the second trimester ultrasound of pregnancy. Postnatal follow-up showed transitory hyperparathyroidism, with hypercalcemia and hypocalciuria. METHODS: Sanger sequencing performed after birth in the three newborns revealed a monoallelic pathogenic variant in the CASR gene, encoding the calcium sensing receptor, confirming the diagnosis of familial hypocalciuric hypercalcemia, paternally inherited. Postnatal evolution was favorable after treatment with a calcimimetic agent. CONCLUSIONS: Previously, prenatal bone abnormalities caused by familial hypocalciuric hypercalcemia had only been described in one patient. This entity should be considered as differential diagnosis of bones abnormalities. Knowing about this unusual etiology is important to guide the diagnosis, the prenatal counseling and to improve medical management.

[Transition of care from childhood and adolescence to adulthood in nephrology]. / Transition de soins de l'enfance et de l'adolescence à l'âge adulte en néphrologie.

For a young patient suffering from a chronic disease, the transition from pediatric to adult care unit is a tricky step, with a high risk of poor therapeutic compliance, loss of follow-up, and possibly tragic consequences. Better knowledge of these risks has led to a strong mobilization of pediatricians and medical teams for adult care over the last ten years, and the notion of health care transition from childhood to adulthood tends to replace simple care transfer. Transition is a step-by-step well-planned process, over several years, aimed at preparing an adolescent to become an independent empowered young adult, and at accompanying him after the change of healthcare team. Chronic renal diseases beginning in childhood have a very different etiological distribution from those occurring in adulthood. They are often rare diseases benefiting from the care of specific reference centers. It is especially for severe renal failure, and more specifically for young transplant recipients, that transition programs have been developed. We describe here the main recommendations and current transition programs.

TITLE: Transition de soins de l'enfance et de l'adolescence à l'âge adulte en néphrologie. ABSTRACT: Pour un jeune adulte atteint d'une maladie chronique, le passage de la médecine pédiatrique à la médecine pour adultes est une étape délicate, avec un risque élevé de mauvaise adhésion thérapeutique et de perte de suivi, dont les conséquences peuvent être dramatiques. Une meilleure connaissance de ces risques a conduit, depuis une dizaine d'années, à une forte mobilisation des pédiatres et des équipes médicales pour adultes. La notion de transition de soins enfant-adulte se substitue au simple transfert. La transition est un processus par étapes, durant plusieurs années, qui vise à préparer un adolescent à devenir un jeune adulte autonome et responsable de sa maladie, et qui inclut un accompagnement après le changement d'équipe du suivi médical. Les maladies rénales chroniques ayant débuté dans l'enfance ont une répartition étiologique bien différente de celles qui surviennent à l'âge adulte, et ce sont souvent des maladies rares bénéficiant des filières de soin spécifiques. C'est surtout pour l'insuffisance rénale sévère et, singulièrement, pour les jeunes transplantés que se sont développés des programmes de transition. Nous décrivons dans cet article les principales recommandations et les programmes existant actuellement.

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.

Benign and malignant proliferation in idiopathic nephrotic syndrome: a French cohort study.

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. A higher resolution version of the Graphical abstract is available as Supplementary information.

National survey of prevention and management of CMV infection in pediatric kidney transplantation in comparison to clinical practice guidelines.

Background: Cytomegalovirus (CMV) is one of the most frequent opportunistic infections in kidney transplant (KT) recipients and is a risk factor for patient and graft survival after KT. Center-to-center variation, optimal prevention and treatment strategies in pediatric KT are currently unknown. This survey aimed to assess current CMV prevention and treatment strategies used among French pediatric KT centers. Methods: A web-based survey was sent to all 13 French pediatric kidney transplantation centers. Results: Twelve (92%) centers responded to the survey. All centers used prophylaxis for the donor-positive/recipient-negative (D+/R-) group. For R + patients, 54% used prophylaxis, 37% used a pre-emptive strategy. In the low-risk group, D-/R-, 50% used a pre-emptive approach and 50% had no specific prevention strategy. The antiviral used by all centers for prophylaxis was valganciclovir (VGCV). The duration of prophylaxis varied from 3 to 7 months and the duration of viral load monitoring varied from 6 months to indefinitely. No center used a hybrid/sequential approach. For the treatment of CMV DNAemia, VGCV or intravenous GCV were used. Therapeutic drug monitoring of VGCV was performed in 5 centers (42%). Five centers reported drug resistance. Eight centers (67%) administered VGCV during the treatment of acute graft rejection. Conclusions: There is uniformity in CMV management in some areas among pediatric KT centers in France but not in others which remain diverse and are not up to date with current guidelines, suggesting unnecessary variation which could be reduced with better evidence to inform practice.

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.

Preemptive Kidney Transplantation Is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.

BACKGROUND: Kidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients. METHODS: We analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first. RESULTS: Patients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses. CONCLUSIONS: In France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease.

Valganciclovir is not associated with decreased EBV infection rate in pediatric kidney transplantation.

Introduction: Primary infection or reactivation of Epstein-Barr Virus (EBV) is a significant cause of morbidity and mortality in pediatric kidney transplantation. Valganciclovir (VGC) treatment is recommended for prophylaxis of cytomegalovirus infection, but its role for the prevention of EBV infection remains controversial. Patients and methods: All pediatric kidney transplant recipients aged <18 years old were considered for inclusion in this retrospective study. EBV negative recipients with an EBV positive donor (a group at risk of primary infection) or EBV positive recipients (a group at risk of reactivation) were included. Severe infection was defined by post-transplant lymphoproliferative disorder (PTLD), symptomatic EBV infection or by asymptomatic EBV infection with a viral load >4.5 log/ml. Outcomes were compared between patients receiving VGC prophylaxis (group P+) and those not receiving VGC prophylaxis (group P-). Results: A total of 79 patients were included, 57 (72%) in the P+ group and 22 (28%) in the P- group; 25 (31%) were at risk of primary infection and 54 (69%) at risk of reactivation. During the first year post-transplant, the occurrence of severe EBV infection was not different between the P+ group (n = 13, 22.8%) and the P- group (n = 5, 22.7%) (p = 0.99). Among patients at risk of primary infection, the rate of severe EBV infection was not different between the two groups (42.1% in P+ vs. 33.3% in P-). A higher frequency of neutropenia was found in the P+ group (66.6%) than in the P- group (33.4%) (p < 0.01). Conclusion: Our observational study suggests no effect of VGC for the prevention of EBV infection in pediatric kidney transplant recipients, irrespective of their EBV status. Adverse effects revealed an increased risk of neutropenia.