Pediatric ANCA vasculitis: clinical presentation, treatment, and outcomes in a French retrospective study.

BACKGROUND: Pediatric ANCA vasculitis is a rare group of diseases with a scarcity of data in children. Annual incidence appeared to increase in the last several years, placing higher interest in the clinical and therapeutical outcomes of the disorder. Also, the growing use of rituximab questions the latest outcomes in these diseases. We therefore conducted a retrospective study to better understand the current characteristics, management, and the latest outcomes of the disorder. METHODS: We conducted a 9-year retrospective study of 46 children in 14 different centers across France to describe their clinical and laboratory presentations, therapeutic regimens, and kidney outcome. RESULTS: P-ANCA appeared to be a potential marker for higher relapse risk. Compared to adults, we found that ear-nose-throat presentations were frequent (45.7%) and more severe. Despite an evolution in the treatment management, kidney outcome remained poor with a substantial proportion of chronic kidney disease (54.8% at 1 year). Mortality stays low with 3 patients (6.5%) deceased at the end of our study. CONCLUSION: Clinical presentation was as previously described and time to diagnosis remains long. P-ANCA is a statistically significant marker for increased relapse risk. We observed a modification in the treatment regimens over the past several years with a growing use of rituximab and a decreasing use of cyclophosphamide. Despite these changes, kidney outcome remains poor and prospective studies should be conducted to assess the most appropriate therapeutic modality for each patient. A higher resolution version of the Graphical abstract is available as Supplementary information.

Treatment and outcome of congenital nephrotic syndrome.

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.

Pharmacokinetics of mycophenolate mofetil in children with lupus and clinical findings in favour of therapeutic drug monitoring.

AIMS: The use of mycophenolate mofetil (MMF) in children with systemic lupus erythematosus (SLE) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to describe mycophenolic acid (MPA, the active moiety of MMF) pharmacokinetics, (ii) to develop a Bayesian estimator (BE) allowing the determination AUC (area under the curve) from a limited number of blood samples and (iii) to explore the relationships between exposure indices to MPA and the clinical status in children with SLE. METHODS: This was a retrospective study including 36 children with SLE, extracted from the expert system ISBA, for whom full- pharmacokinetic profiles of MPA were collected together with clinical data. A pharmacokinetic model and a BE were developed using an iterative two stage Bayesian approach. ROC curve analyses and logistic regressions were used to investigate the association of exposure and active disease. RESULTS: A pharmacokinetic model and a BE were developed that allowed good AUC estimation performance (bias ± SD = -0.02 ± 0.15). ROC curve analyses showed that AUC/dose <0.06 and AUC <4 mg l(-1) h were associated with a good sensitivity and specificity for active disease (78%/94% and 94%/56%, respectively). When introduced in a logistic regression model, AUC <44 mg l(-1) h and AUC/dose <0.06 were associated with an increased risk of active disease (OR = 21.2, 95% CI 2.3, 196.1, P = 0.007 and OR = 59.5, 95% CI 5.9, 588.2, P = 0.0005 respectively]. CONCLUSIONS: The developed pharmacokinetic BE could be used to test prospectively the interest of MPA monitoring for limiting relapse of the disease or its progression.

Hemolytic uremic syndrome related to Shiga-like toxin-producing Escherichia coli with encephalitis hiding a human herpesvirus-6 infection: a case report.

BACKGROUND: Cardiac and neurological involvement in hemolytic uremic syndrome are life-threatening complications. The most frequent complications of cardiac involvement in hemolytic uremic syndrome are myocarditis and cardiac dysfunction due to fluid overload. Pericarditis remains very rare in hemolytic uremic syndrome. To our knowledge, only five cases of cardiac tamponade associated with hemolytic uremic syndrome have been described in literature. A 27-month-old Caucasian girl presented with symptoms of nonbloody diarrhea and tonic-clonic seizures. The diagnosis of Shiga-like toxin-producing Escherichia coli hemolytic uremic syndrome with central nervous system involvement was made, and stool examination revealed infection with a Shiga-like toxin-producing Escherichia coli. She did not need renal replacement therapy but had severe neurological impairment. The patient's course was complicated by pericardial effusion. A pericardiocentesis was performed via an apical approach because the pericardial effusion was predominantly surrounding the left ventricle. Effusion analysis showed an exudate and positivity for human herpesvirus-6B on polymerase chain reaction with viremia. This finding was consistent with primary human herpesvirus-6 infection with encephalitis. CONCLUSION: We report this uncommon case of Shiga-like toxin-producing Escherichia coli hemolytic uremic syndrome associated with a severe human herpesvirus-6 infection. Secondary isolated pericardial effusion and atypical neurological involvement are uncommon in Shiga-like toxin-producing Escherichia coli hemolytic uremic syndrome and should lead the physician to perform additional investigations.

School level of children carrying a HNF1B variant or a deletion.

The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.

The constitutively active V2 receptor mutants conferring NSIAD are weakly sensitive to agonist and antagonist regulation.

Patients having the nephrogenic syndrome of inappropriate antidiuresis present either the R137C or R137L V2 mutated receptor. While the clinical features have been characterized, the molecular mechanisms of functioning of these two mutants remain elusive. In the present study, we compare the pharmacological properties of R137C and R137L mutants with the wild-type and the V2 D136A receptor, the latter being reported as a highly constitutively active receptor. We have performed binding studies, second messenger measurements and BRET experiments in order to evaluate the affinities of the ligands, their agonist and antagonist properties and the ability of the receptors to recruit beta-arrestins, respectively. The R137C and R137L receptors exhibit small constitutive activities regarding the G(s) protein activation. In addition, these two mutants induce a constitutive beta-arrestin recruitment. Of interest, they also exhibit weak sensitivities to agonist and to inverse agonist in term of G(s) protein coupling and beta-arrestin recruitment. The small constitutive activities of the mutants and the weak regulation of their functioning by agonist suggest a poor ability of the antidiuretic function to be adapted to the external stimuli, giving to the environmental factors an importance which can explain some of the phenotypic variability in patients having NSIAD.