Klinefelter Bone Microarchitecture Evolution with Testosterone Replacement Therapy.

Klinefelter Syndrome (KS) patients, defined by a 47 XXY karyotype, have increased risk of fragility fractures. We have assessed bone microarchitecture by high resolution peripheral quantitative CT (HR-pQCT) at the radius and tibia in young KS patients, naïve from testosterone replacement therapy (TRT). Areal bone mineral density (BMD) and body composition were assessed by dual X-ray absorptiometry (DXA). Total testosterone (tT) was measured at baseline. Bone measurements have been repeated after 30 months of TRT. We enrolled 24 KS patients and 72 age-matched controls. KS patients were (mean ± SD) 23.7 ± 7.8 year-old. KS patients had significantly lower relative appendicular lean mass index (RALM) and lower aBMD at spine and hip than controls. Ten patients (42%) had low tT level (≤ 10.4 nmol/L). At baseline, we observed at radius a marked cortical (Ct) impairment reflected by lower Ct.area, Ct.perimeter, and Ct.vBMD than controls. At tibia, in addition to cortical fragility, we also found significant alterations of trabecular (Tb) compartment with lower trabecular bone volume (BV/TV) and Tb.vBMD as compared to controls. After 30 months of TRT, 18 (75%) KS patients were reassessed. Spine aBMD and RALM significantly increased. At radius, both cortical (Ct.Pm, Ct.Ar, Ct.vBMD, Ct.Th) and trabecular (Tb.vBMD) parameters significantly improved. At tibia, the improvement was found only in the cortical compartment. Young TRT naïve KS patients have inadequate bone microarchitecture at both the radius and tibia, which can improve on TRT.

Pediatric renal transplantation: A retrospective single-center study on epidemiology and morbidity due to EBV.

Pediatric R-Tx patients are at high risk of developing EBV primary infection. Although high DNA replication is a risk factor for PTLD, some patients develop PTLD with low viral load. In this retrospective single-center study including all pediatric patients having received R-Tx (2003-2012 period), we aimed to identify risk factors for uncontrolled reactions to EBV (defined as the presence of a viral load >10 000 copies/mL or PTLD). A Cox proportional hazard model was performed. A total of 117 patients underwent R-Tx at a mean age of 9.7 ± 5.3 years, 46 of them being seronegative for EBV at the time of R-Tx. During follow-up, 54 patients displayed positive EBV viral load, 22 of whom presenting with primary infection. An uncontrolled reaction to EBV was observed in 24 patients, whilst 4 patients developed PTLD. Univariate and multivariate analyses suggested the following risk factors for an uncontrolled reaction: age below 5 years, graft from a deceased donor, ≥5 HLA mismatches, EBV-seronegative status at the time of R-Tx, and a secondary post-Tx loss of anti-EBNA. Monitoring anti-EBNA after R-Tx may contribute to the early identification of patients at risk for uncontrolled reaction.

Children and adolescents with cystic fibrosis display moderate bone microarchitecture abnormalities: data from high-resolution peripheral quantitative computed tomography.

We investigated whether bone microstructure assessed by high-resolution peripheral quantitative tomography (HR-pQCT) could be altered in children and teenagers with cystic fibrosis (CF). In comparison to their healthy counterparts, bone microstructure was mildly affected at the tibial level only. INTRODUCTION: Cystic fibrosis-related bone disease (CFBD) may alter bone health, ultimately predisposing patients to bone fractures. Our aim was to assess bone microstructure using high-resolution peripheral quantitative tomography (HR-pQCT) in a cohort of children and teenagers with CF in comparison to age-, puberty-, and gender-matched healthy volunteers (HVs). METHODS: In this single-center, prospective, cross-sectional study, we evaluated the HR-pQCT bone parameters of CF patients and compared them to those of the healthy volunteers. RESULTS: At a median age of 15.4 [range, 10.5-17.9] years, 37 CF patients (21 boys) with 91% [range, 46-138%] median forced expiratory volume in 1 s were included. At the ultradistal tibia, CF patients had a smaller bone cross-sectional area (579 [range, 399-1087] mm2) than HVs (655 [range, 445-981] mm2) (p = 0.027), related to a decreased trabecular area, without any significant differences for height. No other differences were found (trabecular number, separation, thickness, or distribution) at the radial or tibial levels. Bone structure was different in patients receiving ursodeoxycholic acid and those bearing two F508del mutations. CONCLUSION: In our cohort of children and teenagers with good nutritional and lung function status, bone microstructure evaluated with HR-pQCT was not severely affected. Minimal microstructure abnormalities observed at the tibial level may be related to the cystic fibrosis transmembrane conductance regulator defect alone; the long-term consequences of such impairment will require further evaluation.

Serum sclerostin: the missing link in the bone-vessel cross-talk in hemodialysis patients?

UNLABELLED: We found for the first time that in maintenance hemodialysis patients, higher sclerostin serum level was associated with severe abdominal aortic calcification (AAC). In addition, cortical bone microarchitecture (density and thickness) assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at tibia was also independently associated with severe AAC. These results suggest that sclerostin may be involved in the association of mineral and bone disorder with vascular calcification in hemodialysis patients. INTRODUCTION: Severe abdominal aortic calcifications are predictive of high cardiovascular mortality in maintenance hemodialysis (MHD) patients. In patients with end-stage renal disease, a high aortic calcification score was associated with lower bone turnover on bone biopsies. Thus, we hypothesized that sclerostin, a Wnt pathway inhibitor mainly secreted by osteocytes and acting on osteoblasts to reduce bone formation, may be associated with vascular calcifications in MHD patients. METHODS: Fifty-three MHD patients, aged 53 years [35-63] (median [Q1-Q3]) were included. Serum was sampled before the MHD session to assay sclerostin. Framingham score was computed and the abdominal aortic calcification (AAC) score was assessed according to Kauppila method on lateral spine imaging using DEXA. Tibia bone status was evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Patients were distributed into two groups according to their AAC score: patients with mild or without AAC (score below 6) versus patients with severe AAC (score of 6 and above). RESULTS: In multivariate analysis, after adjustment on age, dialysis duration and diabetes, serum sclerostin and cortical thickness were independently associated with severe AAC (odds ratio (OR) = 1.43 for each 0.1 ng/mL increase [95 % confidence interval (CI) 1.10-1.83]; p = 0.006 and 0.16 for 1 SD increase [0.03-0.73]; p = 0.018, respectively). A second cardiovascular model adjusted on Framingham score and the above mentioned confounders showed similar results. CONCLUSIONS: Elevated sclerostin serum level and poorer tibia cortical bone structure by HR-pQCT were positively and independently associated with higher odds of severe AAC in MHD patients. Serum sclerostin may become a biomarker of mineral and bone disorder and vascular risk in MHD patients.

IVIg therapy in the management of BK virus infections in pediatric kidney transplant patients.

BK virus-associated nephropathy (BKPyVAN) induces kidney allograft dysfunction. Although decreasing immunosuppression is the standard for managing BK virus (BKPyV) infection, this strategy is not always effective. The use of polyvalent immunoglobulins (IVIg) may be of interest in this setting. We performed a retrospective single-center evaluation of the management of BKPyV infection in pediatric kidney transplant patients. Among the 171 patients who underwent transplantation between January 2010 and December 2019, 54 patients were excluded (combined transplant n = 15, follow-up in another center n = 35, early postoperative graft loss n= 4). Thus, 117 patients (120 transplants) were included. Overall, 34 (28%) and 15 (13%) transplant recipients displayed positive BKPyV viruria and viremia, respectively. Three had biopsy-confirmed BKPyVAN. The pre-transplant prevalence of CAKUT and HLA antibodies was higher among BKPyV-positive patients compared to non-infected patients. After the detection of BKPyV replication and/or BKPyVAN, the immunosuppressive regimen was modified in 13 (87%) patients: either by decreasing or changing the calcineurin inhibitors (n = 13) and/or switching from mycophenolate mofetil to mTor inhibitors (n = 10). Starting IVIg therapy was based on graft dysfunction or an increase in the viral load despite reduced immunosuppressive regimen. Seven of 15(46%) patients received IVIg. These patients had a higher viral load (5.4 [5.0-6.8]log vs. 3.5 [3.3-3.8]log). In total, 13 of 15 (86%) achieved viral load reduction, five of seven after IVIg therapy. As long as specific antivirals are not available for the management of BKPyV infections in pediatric kidney transplant patients, polyvalent IVIg may be discussed for the management of severe BKPyV viremia, in combination with decreased immunosuppression.

Are plasma proteins a valid alternative for assessing nephrotic syndrome in children from low-income countries?

BACKGROUND: A diagnosis of nephrotic syndrome (NS) in children with edema relies on urinary albumin excretion and usually plasma protein (Pprot) and albumin (Palb) concentrations. METHODS: In order to fit laboratory tests to optimal healthcare in low-resource countries, we established correlations between Pprot and Palb in children with NS (217 measurements in 60 patients) and in children with exudative enteropathy and chronic hepatopathy/liver insufficiency (186 measurements in 21 patients); all patients had repeated measurements at various stages of their disease. RESULTS: There was a good correlation between Pprot and Palb in children with idiopathic NS and genetic NS (ICC=0.8, p < 0.0001, 95% CI: 0.8-0.9 and ICC=0.8, p < 0.0001, 95% CI: 0.7-0.8, respectively), whereas the correlation was average (exudative enteropathy) or absent (chronic hepatopathy) in those without renal protein loss. CONCLUSION: Since Palb measurement is around two times more expensive than Pprot measurement, these results suggest giving priority to total Pprot measurement in the diagnosis and follow-up of children with the NS, mainly in low-resource countries.

Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma: A case report and management of neonatal hypercalcemia: Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma.

Congenital mesoblastic nephroma is a rare pediatric renal tumor and has been reported in patients presenting with palpable abdominal mass, arterial hypertension, hematuria, polyuria, or hypercalcemia. Here we present the case of a 1-month-old neonate with suspected parathyroid hormone (PTH)-related peptide (PTH-rp)-mediated severe hypercalcemia revealing congenital mesoblastic nephroma. Preoperatively, hypercalcemia was corrected with hydration, furosemide, pamidronate, and low-calcium infant formula. Unilateral nephrectomy led to the resolution of hypercalcemia, transient hyperparathyroidism, and transient vitamin D and mineral supplementation. We conclude that congenital mesoblastic nephroma can secrete PTH-rp that can cause severe hypercalcemia.

Vitamin D and calcium intakes in general pediatric populations: A French expert consensus paper.

OBJECTIVES: Nutritional vitamin D supplements are often used in general pediatrics. Here, the aim is to address vitamin D supplementation and calcium nutritional intakes in newborns, infants, children, and adolescents to prevent vitamin D deficiency and rickets in general populations. STUDY DESIGN: We formulated clinical questions relating to the following categories: the Patient (or Population) to whom the recommendation will apply; the Intervention being considered; the Comparison (which may be "no action," placebo, or an alternative intervention); and the Outcomes affected by the intervention (PICO). These PICO elements were arranged into the questions to be addressed in the literature searches. Each PICO question then formed the basis for a statement. The population covered consisted of children aged between 0 and 18 years and premature babies hospitalized in neonatology. Two groups were assembled: a core working group and a voting panel from different scientific pediatric committees from the French Society of Pediatrics and national scientific societies. RESULTS: We present here 35 clinical practice points (CPPs) for the use of native vitamin D therapy (ergocalciferol, vitamin D2 and cholecalciferol, vitamin D3) and calcium nutritional intakes in general pediatric populations. CONCLUSION: This consensus document was developed to provide guidance to health care professionals on the use of nutritional vitamin D and dietary modalities to achieve the recommended calcium intakes in general pediatric populations. These CPPs will be revised periodically. Research recommendations to study key vitamin D outcome measures in children are also suggested.

Guidelines for the management of children at risk of secondary bone fragility: Expert opinion of a French working group.

The current French national guidelines were elaborated by a working group consisting of experts in the field of pediatric endocrinology, rheumatology, hepatogastroenterology, nephrology, and pneumology. A systematic search was undertaken of the literature published between 2008 and 2018 and indexed in PubMed. The recommendations developed were then validated by an external evaluation group comprising representatives from the various highly specialized fields in pediatrics, representatives of the societies and groups supporting the development of the guidelines, and representatives of different healthcare professions. The objective of these guidelines was to detail the current optimal management of children at risk of secondary bone fragility.

[Pediatric nephrology in developing countries]. / Néphrologie pédiatrique dans les pays en développement.

Pediatric nephrology is not a priority medicine in developing countries, but it should improve along with the development of both preventive and curative simple measures since the mortality rate is still important. This can be applied to the management of urinary tract infection, acute nephritis and some other cases of acute renal failure. The identification and management of chronic kidney diseases is mainly based on blood pressure measurement, proteinuria screening and plasma creatinine assessment. However renal replacement therapy (i.e., dialysis and transplantation) is highly expensive and its access is therefore limited to selected growing countries. The improvement in the care of renal children therefore requires better medical knowledge, nurse training and population information.

Pediatric bone evaluation with HR-pQCT: A comparison between standard and height-adjusted positioning protocols in a cohort of teenagers with chronic kidney disease.

BACKGROUND: High-resolution peripheral quantitative computed tomography (HR-pQCT) evaluates different components of bone fragility. The positioning and length of the region of interest (ROI) in growing populations remain to be defined. METHODS: Using HR-pQCT at the ultradistal tibia, we compared a single-center cohort of 28 teenagers with chronic kidney disease (CKD) at a median age of 13.6 (range, 10.2-19.9) years to local age-, gender-, and puberty-matched healthy peers. Because of the potential impact of short stature, bone parameters were assessed on two different leg-length-adjusted ROIs in comparison to the standard analysis, namely the one applied in adults. The results are presented as median (range). RESULTS: After matching, SDS height was -0.9 (-3.3;1.6) and 0.3 (-1.4;2.0) in patients and controls, respectively (P<0.001). In younger children (e.g., prepubertal, n=11), bone texture parameters and bone strength were not different using standard analysis. However, using a height-adjusted ROI enabled better characterization of cortical bone structure. In older patients (e.g., pubertal, n=17), there were no differences for height between patients and controls: with the standard evaluation, cortical bone area and cortical thickness were significantly lower in CKD patients: 85 (50-124) vs. 108 (67-154) mm2 and 0.89 (0.46-1.31) vs 1.09 (0.60-1.62) mm, respectively (both P<0.05). CONCLUSIONS: Adapting the ROI to leg length enables better assessment of bone structure, especially when height discrepancies exist between controls and patients. Larger cohorts are required to prospectively validate this analytic HR-pQCT technique.

Craniosynostosis and metabolic bone disorder. A review.

INTRODUCTION: Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder. MATERIAL AND METHODS: A review of the literature on metabolic forms of craniosynostosis was performed. RESULTS: The most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe. CONCLUSION: The impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.

RMND1 mutations in two siblings: Severe renal hypoplasia but different levels of extrarenal abnormality severity: The ethics of decision making.

Mutations in the RMND1 gene, causing defects in the mitochondrial respiratory chain, result in a very heterozygous phenotype. Currently there are 36 cases reported in the literature. We report two siblings from a non-consanguineous family who were severely affected by a compound heterozygous RMND1 mutation that had not been described previously and were treated differently for their end-stage renal disease. We summarize all previous published cases and focus on the importance of extrarenal comorbidities in the context of therapeutic decision making (renal replacement therapy) and its ethical relevance.

[What about the long-term renal outcome of premature babies?]. / Le rein des anciens prématurés est-il menacé ?

Long-term renal prognosis of expreterm children remains uncertain. The fetal programming theory partially explains adult-onset hypertension, metabolic syndrome and cardiovascular risk in populations of small for gestational age infants. Further studies about long-term renal outcome are warranted because there is a reduction of nephron number in animal models of intrauterine growth restriction (IUGR). An early prevention focused on cardiovascular risks, nutritional mistakes and obesity must be scheduled in populations of expreterm children and IUGR. Since long-term renal outcome is not well known, it may be interesting to perform a regular follow-up of renal parameters (for example: blood pressure, serum creatinine and urinary albumin/creatinine ratio) and to refer children when abnormalities are highlighted.

[Urinary tract infection and antibiotics: oral or intravenous route?]. / Antibiothérapie de l'infection urinaire: orale ou parentérale ?

Management of acute pyelonephritis has long been discussed. The French drug agency (Agence Française de Sécurité Sanitaire des Produits de Santé [AFSSAPS]) has published guidelines for clinical practice in 2007: two to four days of initial parenteral antibiotic therapy followed by oral antibiotics, for a total duration of 10 to 14 days. However, recent data are conflictable and oral antibiotic therapy may be sufficient in some cases. Clinical trials on oral therapy of acute pyelonephritis in selected groups of children are currently ongoing. We suggest following AFSSAPS recommendations in clinical practice until the results of such trials become available. In the future, we can speculate that antibiotic therapy may be reduced in some low risk patients, keeping in mind that around 15% of children with acute pyelonephritis will develop renal scars which may lead to hypertension and microalbuminuria in adulthood.

[Long-term steroid therapy in children: is adjunct therapy relevant in nephrotic syndrome?]. / Corticothérapie prolongée chez l'enfant : quelle place pour un traitement adjuvant dans le syndrome néphrotique ?

The impact of glucocorticoids on bone is specifically relevant in children exposed to a long course of treatment. Corticosteroids lead to a decrease in bone formation, mainly by osteoblastic inhibition in trabecular bone. They also play an indirect role in bone metabolism through systemic actions, such as bone maturation delay, hypogonadism, pubertal delay, and IGF1 inhibition. A systematic review of the literature was conducted. We found 12 clinical trials of interventions including calcium, vitamin D, growth hormone, calcitonin, and bisphosphonates for preventing bone disease in children receiving steroid therapy. There were few randomized controlled trials (n=7), with a limited number of patients, so that a meta-analysis could not be performed. Calcium and vitamin D supplementation may, however, have a beneficial effect on bone in children with nephrotic syndrome receiving long-term steroid therapy. We, therefore, recommend routine vitamin D supplementation, use of steroid-sparing protocols, and global prevention of risk to bone (adequate calcium intake, sun exposure, and physical activity).

[Multicystic dysplastic kidney disease: update and information for parents at the time of prenatal diagnosis]. / Dysplasie rénale multikystique: mise au point et information pour les parents lors du diagnostic anténatal.

Multicystic kidney disease (MCKD) is the most common form of Congenital Abnormality of Kidney and Urinary Tract (CAKUT). This anomaly of renal development is characterized by unilateral enlarged cystic formations and fibrous dysplastic parenchyma. The long-term prognosis is usually good; however because of reduced nephron mass, an early prevention of cardiovascular risk and nephrotoxicity is recommended. A lifelong follow-up of blood pressure, serum creatinine and microalbuminuria seems logical as well as in other patients with a single kidney. MCKD is usually diagnosed during pregnancy so that parents often question about long-term prognosis and follow-up. Therefore, we propose an information sheet for parents.

[Blueberry Muffin Baby and spontaneous remission of neonatal leukaemia]. / Leucémie aiguë néonatale et Blueberry Muffin syndrome: à propos d'un cas spontanément régressif.

Blueberry Muffin baby is a rare neonatal skin disorder. Many causes are known, examples are congenital infections, hemolysis and tumors. We report on a newborn presenting with Blueberry Muffin syndrome and an adrenal mass which lead to the diagnosis of neuroblastoma. Actually, it corresponded to an acute monoblastic leukaemia with an adrenal localization and a cerebrospinal fluid involvement. Leukaemia should always be considered in such patients, even in the absence of blasts on white blood cells count and bone marrow examination, as in this patient. This observation was also unusual due to spontaneous remission. The patient is in complete remission at 1 year follow-up.

Eculizumab and thrombotic microangiopathy after hematopoietic stem cell transplantation: A report on its efficacy and safety in two pediatric patients.

BACKGROUND: Thrombotic microangiopathy (TMA) is a severe complication after hematopoietic stem cell transplantation (HSCT), with the reported mortality rate in such cases usually reaching 90%. CASES: We report on two pediatric cases of patients successfully treated by eculizumab for severe HSCT-TMA, occurring in two girls (8.4 and 3.6 years). The first patient developed TMA with hematologic abnormalities and renal/pulmonary lesions after allogeneic HSCT for Philadelphia-positive acute lymphoblastic leukemia; she received eculizumab 7 months after HSCT, with a dramatic improvement of renal function. The second patient developed severe TMA (cardiac tamponade, renal failure requiring dialysis, gastritis) after autologous HSCT for metastatic neuroblastoma. She received eculizumab for 7 months, with a dramatic improvement of renal function. No side effects were observed. CONCLUSION: The use of eculizumab as first-line therapy in pediatric patients with severe HSCT-TMA with multisystemic lesions appears promising. Larger international studies are required to confirm its benefit and safety for this specific indication.

[Renal tubular dysgenesis and mutation in the renin gene]. / Dysgénésie tubulaire proximale et mutation du gène de la rénine.

Renal tubular dysgenesis is a severe and rare disorder of the renal development characterized by fetal anuria, oligohydramnios and early death from pulmonary hypoplasia and refractory arterial hypotension. We report on a female patient who presented with anuria in the neonatal period, requiring peritoneal dialysis until 5 months of age with unexpected diuresis recovery at 2 months of age. Clinical, histological and pathophysiological issues are discussed for this disease related to a mutation in the renin gene.