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.

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.

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.

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.

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.

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.

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.

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.

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.

[Renal abnormalities in Down syndrome: A review]. / Atteintes rénales de la trisomies 21.

Down syndrome (DS) is often associated with cardiac malformations, so that kidney damage is little known. The objective of this study was to present the diversity of renal abnormalities and their potential progression to chronic renal failure. Among congenital abnormalities of the kidney and urinary tract (CAKUT) abnormalities appear to be frequent: pyelectasis, megaureters, posterior urethra valves, as well as renal malformations such as renal hypoplasia, horseshoe kidney, or renal ectopia. Contributing factors to acute kidney failure have been described in patients with DS: bilateral lesions and minor renal injury, such as glomerular microcysts, tubular dilation, and immature glomeruli. Histological lesions can be found, albeit nonspecific; they occur earlier than in the general population. Two metabolic specificities have also been described: decreased clearance of uric acid and a hypercalciuria by passive hyperabsorption. End-stage renal disease can occur, thus raising the problem of the best choice of management. In conclusion, renal abnormalities in patients in DS should be known so as to preserve a good renal functional prognosis: systematic screening with renal ultrasound can be proposed.

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.

[Neonatal intoxication to vitamin D in premature babies: A series of 16 cases]. / Intoxication néonatale à la vitamine D chez des anciens prématurés : une série de 16 cas.

INTRODUCTION: Preterm neonates are particularly at risk of vitamin D (25-D) deficiency. To prevent rickets and osteopenia in this population, international guidelines vary between 800 and 1000IU per day of vitamin D in Europe and recommend 400IU per day in the USA. Target levels of circulating 25-D are not well identified, with the lower target level 50-75nmol/L and the upper target level probably 120nmol/L. METHODS: Between 2013 and 2015, 16 premature infants (born<35WG) were referred to pediatric nephrology clinics because of symptoms secondary to 25-D overdose during the neonatal period. Clinical and biological data were retrospectively reviewed to better define this population. The results are presented as the median (range). RESULTS: Gestational age was 27 (24-35)WG with a birth weight of 810 (560-2120)g. Nephrocalcinosis was the initial symptom in 37% of cases, hypercalcemia in 44%, and hypercalciuria in 19%. Daily vitamin D doses were 333 (35-676)IU. Age and body weight at initial symptom were 36.6 (27.6-47.6)WG and 2300 (640-3760)g, respectively. The 25-D level at the time of the first dosage was 210 (119-350)nmol/L and the 1-25 vitamin D level was 370 (245-718)pmol/L (local normal values for age<240). During follow-up, 12 patients displayed nephrocalcinosis, ten hypercalciuria, and three hypercalcemia. The 25-D level normalized in ten patients within 10 (3-32)months after vitamin D withdrawal. Nephrocalcinosis improved in ten of 12 patients, within 12 (3-30)months. Vitamin D could be readministered in ten patients. When searched (n=3), no CYP24A1 mutation was identified in two patients, but was identified in the heterozygous state in one. CONCLUSION: A 25-D overdose should be systematically ruled out in the presence of nephrocalcinosis, hypercalcemia, and/or hypercalciuria during infancy in children born preterm. Studies are required to assess the exact frequency of 25-D deficiency and overdose in this population, as well as to evaluate the potential deleterious effects of this imbalance on bone, kidney, and brain development.

Renal impairment in hypophosphatasia.

Renal impairment in hypophosphatasia (HPP) has been described but remains poorly understood: hypercalciuria, nephrocalcinosis and sometimes even chronic kidney failure secondary to chronic hypercalcemia/hypercalciuria or exposure to toxic agents. The objectives of this review are to describe the different renal lesions observed in HPP, and the therapeutic measures that can be applied (in particular, thiazide diuretics).

[Diagnosis and management of chronic kidney disease in children: Guidelines of the French Society of Pediatric Nephrology]. / Diagnostic et prise en charge de la maladie rénale chronique de l'enfant : recommandations de la Société de néphrologie pédiatrique (SNP).

These guidelines are intended to assist physicians in the care of children with chronic kidney disease (CKD), defined in children as in adults, regardless of its cause. Often silent for a long time, CKD can evolve to chronic renal failure or end-stage renal disease. Its management aims at slowing disease progression and treating CKD complications as soon as they appear. The different aspects of pediatric CKD care are addressed in these guidelines (screening, treatment, monitoring, diet, quality of life) as proposed by the French Society of Pediatric Nephrology. Highly specialized care provided in the hospital setting by pediatric nephrologists is not detailed.

[Insights into cystic fibrosis-related bone disease]. / Maladie osseuse liée à la mucoviscidose : mise au point.

With the increasing life expectancy of patients with cystic fibrosis (CF), prevalence of late complications such as CF-related bone disease (CFBD) has increased. It was initially described in 24% of the adult population with CF and has also been reported in the pediatric population. CFBD is multifactorial and progresses in different steps. Both decreased bone formation and increased bone resorption (in different amounts) are observed. CFBD is likely primitive (directly related to the CFTR defect itself), but is also worsened by acquired secondary factors such as lung infections, chronic inflammation, denutrition, vitamin deficiency, and decreased physical activity. CFBD may be clinically apparent (i.e., mainly vertebral and costal fractures), or clinically asymptomatic (therefore corresponding to abnormalities in bone density and architecture). CFBD management mainly aims to prevent the occurrence of fractures. Prevention and regular monitoring of bone disease as early as 8 years of age is of the utmost importance, as is the control of possible secondary deleterious CFBD factors. New radiological tools, such as high-resolution peripheral quantitative computed tomography, allow an accurate evaluation of cortical and trabecular bone micro-architecture in addition to compartmental density; as such, they will likely improve the assessment of the bone fracture threat in CF patients in the near future.

Neonatal transient hypophosphatemic hypercalciuric rickets in dizygous twins: A role for maternal alendronate therapy before pregnancy or antireflux medications?

BACKGROUND: Bisphosphonates (BP) are sometimes used in children and young women, but their use requires expertise and caution due to the relative lack of long-term efficacy and safety data. CLINICAL CASES: We report on two dizygotic male twins with a past of mild prematurity who presented at the age of 2 months with moderate clinical craniotabes, hypophosphatemia, normal circulating calcium, severe hypercalciuria, and low parathyroid hormone levels. Following supplementation with oral phosphorus and native vitamin D, the clinical and biological abnormalities disappeared within 2 months. Since the twins were dizygotic and were identical in terms of clinical presentation and progression, the only likely explanation for these transient mineral abnormalities was prenatal or neonatal exposure to a toxic agent. Taking into account their medical past, two drugs were possibly involved: either oral alendronate that their mother had received before pregnancy for misdiagnosed osteoporosis or antireflux medications, or both. DISCUSSION: We believe that these two cases could correspond to the first description of a potential mother-to-fetus transmission of alendronate, inducing early and transient hypophosphatemic rickets, the clinical picture being worsened by the antireflux drugs impairing intestinal phosphate absorption. For pediatric rheumatologists, this raises the question of more clearly defining the indications for BP in female children and teenagers; for rheumatologists, this also demonstrates the importance of correctly diagnosing osteoporosis and not using BP off-label, especially in women of child-bearing age.

[Vitamin D supplementation: not too much, not too little!]. / Supplémentation en vitamine D : ni trop, ni trop peu !

Vitamin D deficiency is common in the general population and even more frequent in patients with chronic diseases. The prevention of rickets with native vitamin D supplementation is one of the oldest and most effective prophylactic measures ever reported in medicine, leading to an almost complete eradication of vitamin D-deficient rickets in developed countries. We report on two children with vitamin D abnormalities: the first, 10-year-old child developed rickets without any vitamin D supplementation despite different risk factors (autism, ethnicity, nutritional problems, chronic antiepileptic therapies). In contrast, the second, 8-month-old child received double doses of native vitamin D from birth for several months and was referred for acute and symptomatic hypercalcemia. As such, vitamin D supplementation must follow specific rules: neither too much nor too little! We also discuss the emergence of "new" genetic diseases such as mutations in the 24-hydroxylase (CYP24A1) gene inducing neonatal hypercalcemia and nephrocalcinosis: we believe that before prescribing conventional vitamin D supplementation as recommended by the national guidelines, pediatricians should quickly rule out a potential genetic abnormality in phosphate/calcium metabolism (namely a history of lithiasis or hypercalcemia) that would lead to further biological investigations.