Monitoring of Adverse Events and Safety in Autoinflammatory Diseases: Real-Life Data from the Eurofever Registry.

OBJECTIVES: The study is aimed to evaluate the impact of safety events in the Eurofever registry for Autoinflammatory diseases. METHODS: This was a retrospective and longitudinal observational multicentre study. Data were retrieved from the international registry Eurofever, starting patients' enrolment since 2009. All moderate, severe, or very severe AEs reported by treating physician in Eurofever were analyzed regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities. RESULTS: Complete information on safety were available in 2464 patients enrolled in the registry. In 1499 of them retrospective data encompassing the period from disease onset to enrolment were available, whereas 965 consecutive patients entered in the longitudinal part of the study. A total of 479 AEs have been reported in 275 patients. Eighty-two AEs were reported as serious and 99 were drug-related according to the physicians. Infections or infestations (94; 19.6%), gastrointestinal disorders (66; 13.8%), nervous system disorders (41; 8.6%) and systemic disorders or administration site reactions (35; 7.3%) were the most frequent reported events. The highest absolute number of drug-related AEs were related to biologic DMARDs (40/99 reports, 40,4%) and colchicine (31/99 reports, 31.3%). CONCLUSIONS: Present study shows the importance of a longitudinal and homogeneous registration of the AEs in rare conditions, with a particular focus on the safety profile of the treatments used in these conditions.

Monogenic lupus due to spondyloenchondrodysplasia with spastic paraparesis and intracranial calcification: case-based review.

Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia characterized with platyspondyly and metaphyseal lesions of the long bones mimicking enchondromatosis, resulting in short stature. SPENCD often coexists with neurologic disorders and immune dysregulation. Spasticity, developmental delay and intracranial calcification are main neurologic abnormalities. Large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders with autoimmune thrombocytopenia and systemic lupus erythematosus as the most common phenotypes. SPENCD is caused by loss of tartrate-resistant acid phosphatase (TRAP) activity, due to homozygous mutations in ACP5, playing a role in non-nucleic acid-related stimulation/regulation of the type I interferon pathway. We present two siblings, 13-year-old girl and 25-year-old boy with SPENCD, from consanguineous parents. Both patients had short stature, platyspondyly, metaphyseal changes, spastic paraparesis, mild intellectual disability, and juvenile-onset SLE. The age at disease-onset was 2 years for girl and 19 years for boy. Both had skin and mucosa involvement. The age at diagnosis of SLE was 4 years for girl, and 19 years for boy. The clinical diagnosis of SPENCD was confirmed by sequencing of ACP5 gene, which revealed a homozygous c.155A > C (p.K52T), a variant reported before as pathogenic. Juvenile-onset SLE accounts for about 15-20% of all SLE cases. But, the onset of SLE before 5-years of age and also monogenic SLE are rare. Our case report and the literature review show the importance of multisystemic evaluation in the diagnosis of SPENCD and to remind the necessity of investigating the monogenic etiology in early-onset and familial SLE cases.

Treatment and long-term outcome in primary distal renal tubular acidosis.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. METHODS: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. RESULTS: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. CONCLUSION: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.

Outcome of posterior urethral valve in 64 children: a single center's 22-year experience.

BACKGROUND: Posterior urethral valve (PUV) is the most serious form of congenital anomalies of kidney and urinary tract (CAKUT) in boys with significant risk of progression to chronic kidney disease (CKD). We present our long-term results in children with PUV. METHODS: Retrospective chart review of 113 children with PUV followed within the years of 1996-2018 was performed. Clinical, laboratory and epidemiologic parameters were analyzed for their impact on renal outcome. RESULTS: The median age of diagnosis was 1.00 month (1.00-132.00) and the median follow-up period was 70 months (60.00-216.00). Antenatal diagnosis was present in 33 patients (51.5%) mainly with bilateral hydronephrosis and oligohydramnios. The most common postnatal presentation was recurrent urinary tract infection (UTI) in 14 cases (21.9%) and incontinence in three cases (4.7%). Vesicoureteral-reflux (VUR) was present in 31 cases (48.4%). All patients had surgery and urinary diversion was needed in 18 (28.2%). Varying stages of chronic kidney disease (CKD) developed in 23 cases (35.9%) and rise in serum creatinine was especially prominent after the 4th year of follow-up. Of 23 CKD patients, seven (10.9%) were in ESRD and on dialysis. Mortality occurred in one (1.5%) patient. Hypertension, proteinuria and high initial serum creatinine (>1.28 mg/dL) were statistically significant risk factors for CKD, as expected. Surprisingly VUR and UTI did not show such a significant impact on CKD development. Antenatal detection was with significantly less risk for CKD. CONCLUSIONS: Our results confirm that PUV has a considerable risk for CKD development. Antenatal diagnosis, management of proteinuria and hypertension may modify this progression. But already injured kidneys still have a potential risk. The need for further research to evaluate the impact of any intervention on long term renal outcome is obvious.

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome.

BACKGROUND: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. METHODS: Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. RESULTS: Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing. CONCLUSIONS: Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

Childhood urinary tract infection caused by extended-spectrum ß-lactamase-producing bacteria: Risk factors and empiric therapy.

BACKGROUND: This study investigated risk factors of childhood urinary tract infection (UTI) associated with extended-spectrum ß-lactamase (ESBL)-producing bacteria (ESBL-positive UTI) and evaluated antimicrobial resistance as well as empiric treatment of childhood UTI. METHODS: The records of children with positive urine culture between 1 January 2008 and 31 December 2012 were evaluated. Patients with positive urine culture for ESBL-producing bacteria were defined as the ESBL-positive group, whereas patients of the same gender and similar age with positive urine culture for non-ESBL-producing bacteria were defined as the ESBL-negative group. Each ESBL-positive patient was matched with two ESBL-negative patients. RESULTS: The ESBL-positive and negative groups consisted of 154 and 308 patients, respectively. Potential risk factors for ESBL-positive UTI were identified as presence of underlying disease, clean intermittent catheterization (CIC), hospitalization, use of any antibiotic and history of infection in the last 3 months (P < 0.05). On logistic regression analysis, CIC, hospitalization and history of infection in the last 3 months were identified as independent risk factors. In the present study, 324 of 462 patients had empiric therapy. Empiric therapy was inappropriate in 90.3% of the ESBL-positive group and in 4.5% of the ESBL-negative group. Resistance to nitrofurantoin was similar between groups (5.1% vs 1.2%, P = 0.072); resistance to amikacin was low in the ESBL-positive group (2.6%) and there was no resistance in the ESBL-negative group. CONCLUSIONS: Clean intermittent catheterization, hospitalization and history of infection in the last 3 months should be considered as risk factors for ESBL-positive UTI. The combination of ampicillin plus amikacin should be taken into consideration for empiric therapy in patients with acute pyelonephritis who have the risk factors for ESBL-positive UTI. Nitrofurantoin seems to be a logical choice for the empiric therapy of cystitis.

Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever--a randomized controlled noninferiority trial.

BACKGROUND: In this study, we examined the efficacy and safety of a once-daily dosage schema of colchicine compared with a twice-daily dosage schema in pediatric patients with familial Mediterranean fever (FMF). METHODS: In this 24-week, multicenter, randomized controlled noninferiority trial, pediatric patients newly diagnosed with FMF carrying a homozygous or compound heterozygous mutation and not receiving any treatment were included. Patients were randomly assigned using a block randomization method to receive treatment with a once- or twice-daily dosage. Clinical and laboratory characteristics and medication side effects were recorded and compared between groups. The study was carried out in compliance with Good Clinical Practice and the Consolidated Standards for Reporting of Trials (CONSORT) statement. RESULTS: A total of 92 patients were selected, and 79 patients completed the study. There were 42 patients in the once-daily dosage group and 37 in the twice-daily dosage group. The results indicated that the once-daily dosage was not inferior to the twice-daily dosage regarding decrease in attack frequency and duration as well as improvement in clinical findings and Mor severity scores. Alterations in laboratory findings indicating inflammation, such as erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A, were similar in both groups. The rates of drug side effects were similar between the once- and twice-daily dosage groups, implying comparable safety of colchicine, with the exception of diarrhea, which was slightly higher in the once-daily dosage group. CONCLUSIONS: Using colchicine with either a once- or twice-daily dosage provides similar clinical and laboratory improvements. Considering both efficacy and safety, colchicine can be prescribed with a once-daily dosage. TRIAL REGISTRATION ID: ClinicalTrials.gov identifier NCT02602028 . Registered 5 November 2015.

Effect of cholecalciferol on local arterial stiffness and endothelial dysfunction in children with chronic kidney disease.

BACKGROUND: As cardiovascular factors are the leading cause of mortality in chronic kidney disease (CKD) and as vitamin D deficiency is prevalent in this population, we aimed to examine the effect of oral cholecalciferol on cardiac parameters and biomarkers for endothelial cell activation in children with CKD. METHODS: Forty-one children with CKD and 24 healthy subjects free of any underlying cardiac or renal disease with low 25-hydroxyvitamin D3 (25OHD) levels were evaluated using echocardiography basally and following Stoss vitamin D supplementation. The local vascular stiffness and endothelial dysfunction markers were compared among the groups. RESULTS: Initial flow-mediated dilatation (FMD) measurements were lower and local arterial stiffness was significantly higher in patients. After vitamin D supplementation, these improved significantly in patients, while no significant change was observed for the healthy group. Homocysteine showed inverse correlation with baseline vitamin D level in CKD children and von Willebrand factor emerged as an independent risk factor for FMD impairment. CONCLUSIONS: Our interventional study revealed the favorable effects of high-dose cholecalciferol on cardiovascular and endothelial parameters, implying the importance of vitamin D supplementation in children with CKD.

Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome.

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.

Hemolytic uremic syndrome outbreak in Turkey in 2011.

The aim of this retrospective multicenter study was to define the epidemiological and clinical features and prognostic factors of the first diarrhea-related hemolytic uremic syndrome (D+HUS) outbreak in Turkey in 2011. All pediatric nephrology centers in Turkey were asked about D+HUS patients via e-mail. Seventy D+HUS patients (median age: 5.7 years) participated. The seasonal peak was around the 7th, 8th and 9th months with 44 cases, centered in the east Marmara region. No causative agent could be identified. The rate of neurological complications and mortality was 21.4% and 4.2%, respectively. Eculizumab was used in four cases. Two of them had severe neurological complications despite plasma exchange. Elevated polymorphonuclear leukocyte count during hospital admission was the predictor of both severe disease and poor outcome. Duration of prodrome was the predictor of poor outcome (p<0.05). In conclusion, the median age of the affected children was greater than in the previous reports, while clinical features and outcome were similar.

A case of SCNN1A splicing mutation presenting as mild systemic pseudohypoaldosteronism type 1.

Systemic pseudohypoaldosteronism type 1 (PHA1) is characterized by excessive salt loss from the renal tubulus, colon, sweat and salivary glands. Here we present a case of systemic PHA1 whose genetic analysis revealed a homozygous splicing mutation in intron 4 of SCNN1A (c.684+2 T>A) and discuss with the patient's phenotype. Previously described systemic PHA cases show varying degrees of severity dependent on the mutation. Most of the SCNN1A gene mutations present with a severe phenotype. The long-term follow-up and phenotype of the two reported cases with splicing mutation of the SCNN1A gene are unknown. Our case, with a new splicing mutation of SCNN1A, presented with a severe phenotype in the neonatal period. Since then she has been well without any hospitalization and respiratory illness. Her requirement for medication also decreased gradually. After early infancy she presented a mild systemic PHA1 phenotype up to the age of 39 months. In conclusion, the mutation in the patient is located at the splicing site and is definitely a new and pathogenic one, and the phenotype of the patient was milder as observed in a patient with missense mutation.

Urinary tract infection prophylaxis in children with neurogenic bladder with cranberry capsules: randomized controlled trial.

Objectives. The aim of this randomized controlled prospective study is to evaluate the efficacy of cranberry capsules for prevention of UTI in children with neurogenic bladder caused by myelomeningocele. Patients and Methods. To be eligible for this study, patients had to be diagnosed as neurogenic bladder caused by myelomeningocele, evaluated urodynamically, followed up with clean intermittent catheterization and anticholinergic drugs. Intervention. Six months of treatment with placebo; after a week of wash-out period treatment of cranberry extract tablets (1 capsule/day) for an additional 6 months. Randomization was performed sequentially. Patients and care givers were blinded to drug assignment. Main outcome measure was infection rate. Group comparisons were performed with Wilcoxon test. Results. The study population included 20 (F/M: 13/7) patients with neurogenic bladder with the mean age of 7.25 ± 3.49 (4, 18) years. The median UTI rate was 0.5/year during placebo usage whereas 0/year during cranberry capsule usage. Decrease in infection rate was significant with cranberry capsule usage (P = 0.012). Decrease in the percentage of the pyuria was also recorded as significant (P = 0.000). Any adverse events or side effects were not recorded. Conclusion. We concluded that cranberry capsules could be an encouraging option for the prevention of recurrent UTI in children with neurogenic bladder caused by myelomeningocele.

Hypomagnesemia-hypercalciuria-nephrocalcinosis and ocular findings: a new claudin-19 mutation.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive syndrome that affects the tight junction proteins claudin-16 and claudin-19 in the thick ascending limb. In patients with claudin-19 mutations, additional symptoms such as visual impairment and other ophthalmologic findings are expected. In this report, we present a seven-year-old girl with polyuria and polydipsia. She was the daughter of consanguineous parents with a history of neonatal hypomagnesemic convulsion. On physical examination, bilateral horizontal nystagmus, retinitis pigmentosa and severe myopia were detected. Laboratory examination revealed hypomagnesemia, hypercalciuria and hypermagnesuria. A clinical diagnosis of FHHNC caused possibly by claudin-19 mutation was decided with the ocular findings. DNA analysis revealed a novel homozygous nonsense mutation (W169X) in the CLDN19 gene. In conclusion, in a patient with consanguineous parents, history of hypomagnesemic convulsion and disturbed organization and development of the retina, a diagnosis of FHHNC caused by claudin-19 mutation should be considered.