Circulating autotaxin levels in healthy teenagers: Data from the Vitados cohort.

Autotaxin (ATX) is a secreted enzyme with a lysophospholipase D activity, mainly secreted by adipocytes and widely expressed. Its major function is to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), an essential bioactive lipid involved in multiple cell processes. The ATX-LPA axis is increasingly studied because of its involvement in numerous pathological conditions, more specifically in inflammatory or neoplastic diseases, and in obesity. Circulating ATX levels gradually increase with the stage of some pathologies, such as liver fibrosis, thus making them a potentially interesting non-invasive marker for fibrosis estimation. Normal circulating levels of ATX have been established in healthy adults, but no data exist at the pediatric age. The aim of our study is to describe the physiological concentrations of circulating ATX levels in healthy teenagers through a secondary analysis of the VITADOS cohort. Our study included 38 teenagers of Caucasian origin (12 males, 26 females). Their median age was 13 years for males and 14 years for females, ranging from Tanner 1 to 5. BMI was at the 25th percentile for males and 54th percentile for females, and median blood pressure was normal. ATX median levels were 1,049 (450-2201) ng/ml. There was no difference in ATX levels between sexes in teenagers, which was in contrast to the male and female differences described in the adult population. ATX levels significantly decreased with age and pubertal status, reaching adult levels at the end of puberty. Our study also suggested positive correlations between ATX levels and blood pressure (BP), lipid metabolism, and bone biomarkers. However, except for LDL cholesterol, these factors were also significantly correlated with age, which might be a confounding factor. Still, a correlation between ATX and diastolic BP was described in obese adult patients. No correlation was found between ATX levels and inflammatory marker C-reactive protein (CRP), Body Mass Index (BMI), and biomarkers of phosphate/calcium metabolism. In conclusion, our study is the first to describe the decline in ATX levels with puberty and the physiological concentrations of ATX levels in healthy teenagers. It will be of utmost importance when performing clinical studies in children with chronic diseases to keep these kinetics in mind, as circulating ATX might become a non-invasive prognostic biomarker in pediatric chronic diseases.

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

INTRODUCTION: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking. The objective of this study was to describe characteristics and outcomes to search for a phenotype-genotype correlation. METHODS: We retrospectively collected clinical data, genetic features, and outcomes from 24 genetically confirmed cases from 10 French centers; results are presented as median (min-max). RESULTS: Clinical symptoms at diagnosis (age, 1.5 [0.5-8.7] years) were mainly bone and neurological abnormalities, and laboratory data showed hypocalcemia (1.97 [1.40-2.40] mmol/L), hypophosphatemia (-3.4 [-13.4 to (-)0.2] SD score for age), low 25OHD and low 1,25(OH)2D3, secondary hyperparathyroidism with PTH at 6.6 (1.3-13.7) times the upper limit for normal (ULN; PTH expressed as ULN to homogenize data presentation), and increased alkaline phosphatase (1968 [521-7000] IU/L). Bone radiographs were abnormal in 83% of patients. We identified 17 variations (11 missense, 3 frameshift, 2 truncating, and 1 acceptor splice site variations) in 19 families (homozygous state in 58% [11/19]). The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase (759 vs 2082 IU/L). Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical, and radiological outcomes were satisfactory, and complications occurred if there was bad adherence. CONCLUSION: Overall, our findings highlight good outcomes under substitutive treatment and the need of a closer follow-up of eyes, teeth, kidneys, and blood pressure in VDDR1A.

X-Linked Hypophosphatemia, Not Only a Skeletal Disease But Also a Chronic Inflammatory State.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare genetic disease caused by a primary excess of fibroblast growth factor 23 (FGF23). FGF23 has been associated with inflammation and impaired osteoclastogenesis, but these pathways have not been investigated in XLH. OBJECTIVE: This work aimed to evaluate whether XLH patients display peculiar inflammatory profile and increased osteoclastic activity. METHODS: We performed a prospective, multicenter, cross-sectional study analyzing transcript expression of 8 inflammatory markers (Il6, Il8, Il1ß, CXCL1, CCL2, CXCR3, Il1R, Il6R) by real-time quantitative polymerase chain reaction on peripheral blood mononuclear cells (PBMCs) purified from total blood samples extracted from patients and healthy control individuals. The effect of native/active vitamin D on osteoclast formation was also assessed in vitro from XLH patients' PBMCs. RESULTS: In total, 28 XLH patients (17 children, among them 6 undergoing standard of care [SOC] and 11 burosumab therapy) and 19 controls were enrolled. Expression of most inflammatory markers was significantly increased in PBMCs from XLH patients compared to controls. No differences were observed between the burosumab and SOC subgroups. Osteoclast formation was significantly impaired in XLH patients. XLH mature osteoclasts displayed higher levels of inflammatory markers, being however lower in cells derived from the burosumab subgroup (as opposed to SOC). CONCLUSION: We describe for the first time a peculiar inflammatory profile in XLH. Since XLH patients have a propensity to develop arterial hypertension, obesity, and enthesopathies, and because inflammation can worsen these clinical outcomes, we hypothesize that inflammation may play a critical role in these extraskeletal complications of XLH.

The effect of lumasiran therapy for primary hyperoxaluria type 1 in small infants.

BACKGROUND: Lumasiran, a sub-cutaneous RNA-interference therapy, has been recently approved for primary hyperoxaluria type 1 (PH1), with doses and intervals according to body weight. Little is known as to its use in infants; the aim of this study was to describe treatment outcome in 3 infants who received lumasiran therapy before 2 years of age. CASE-DIAGNOSIS/TREATMENT: Patient 1 was diagnosed antenatally and received lumasiran from day 9. According to the product information template (PIT), he received monthly lumasiran (3 times at 6 mg/kg, then 3 mg/kg), with hyperhydration and potassium citrate. Despite decreased plasma oxalate levels, persistent normal kidney function, and good tolerance, kidney ultrasound performed after 2 months found nephrocalcinosis, without normalization of urinary oxalate (UOx). The dose was increased back to 6 mg/kg, inducing a normalization in UOx. Nephrocalcinosis started to improve at month 10. Patient 2 was diagnosed at 2.5 months (acute kidney failure); nephrocalcinosis was present from diagnosis. She received monthly lumasiran (6 mg/kg), with progressive decrease in UOx and substantial improvement in kidney function but stable nephrocalcinosis after 9 injections. Patient 3 was diagnosed fortuitously (nephrocalcinosis) at 3.5 months and received lumasiran before genetic diagnosis, leading to decreased UOx and maintenance of normal kidney function. Nephrocalcinosis improved after 5 injections. CONCLUSIONS: This report presents the youngest children treated with lumasiran worldwide. Lumasiran seems effective without side effects in infants but does not completely prevent the onset of nephrocalcinosis in the most severe forms. Higher doses than those proposed in the PIT might be required because of hepatic immaturity.

Peripheral Blood Mononuclear Cells (PBMCs) to Dissect the Underlying Mechanisms of Bone Disease in Chronic Kidney Disease and Rare Renal Diseases.

PURPOSE OF REVIEW: To describe the methods that can be used to obtain functional and mature osteoclasts from peripheral blood mononuclear cells (PBMCs) and report the data obtained with this model in two peculiar diseases, namely pediatric chronic kidney disease-associated mineral and bone disorders (CKD-MBD) and nephropathic cystinosis. To discuss future research possibilities in the field. RECENT FINDINGS: Bone tissue undergoes continuous remodeling throughout life to maintain bone architecture; it involves two processes: bone formation and bone resorption with the coordinated activity of osteoblasts, osteoclasts, and osteocytes. Animal models fail to fully explain human bone pathophysiology during chronic kidney disease, mainly due to interspecies differences. The development of in vitro models has permitted to mimic human bone-related diseases as an alternative to in vivo models. Since 1997, osteoclasts have been generated in cell cultures, notably when culturing PBMCs with specific growth factors and cytokines (i.e., M-CSF and RANK-L), without the need for osteoblasts or stromal cells. These models may improve the global understanding of bone pathophysiology. They can be been used not only to evaluate the direct effects of cytokines, hormones, cells, or drugs on bone remodeling during CKD-MBD, but also in peculiar genetic renal diseases inducing specific bone impairment.