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.

[Factors influencing the acceptability of pediatric galenic formulations]. / Facteurs influençant l'acceptabilité des formulations galéniques en pédiatrie ­ revue de la littérature.

BACKGROUND AND GOAL OF THIS STUDY: Few available galenic formulations of drugs have pediatric doses, so that many of them are used off label in children. The influence of such pharmaceutical formulation on therapeutic adherence was evaluated in a systematic review of the literature. MATERIALS AND METHODS: This search was performed in 4 data bases: Medline, the Cochrane Library, Web of Science and Science Direct. Included articles were in French or English and focused on therapeutic adherence and route of administration. RESULTS: Overall, 51 articles were included in the study: 46 from Medline (27 selected), 1 from The Cochrane Library (1 duplicate), 61 from Web of Science (13 selected) and 23 articles from Science Direct (11 selected). The two main pharmaceutical formulations studied were liquid dosage form 51% (n=28) and solid oral form 35% (n=19). DISCUSSION: Easy use of liquid forms (n=18) (easy dose adjustment and administration) was associated with good adherence. Optimization of organoleptic properties was found to improve adherence (n=20). The main limitations to the use of solid oral formulations are the risk of choking in a child under 6 and difficulty adapting doses for pediatric use. Commercialization of minitablets should help solve these problems (n=3) and therapeutic education sessions could make it possible to prescribe selected pills to children aged 4 or older (n=2). A risk of misuse because of incorrect administration seems to be the reason that aerosols are underused. CONCLUSION: Drug formulation influences therapeutic adherence in children, which is a cornerstone for successful pharmacotherapeutic management.

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.

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.

Oral drug dosage forms administered to hospitalized children: Analysis of 117,665 oral administrations in a French paediatric hospital over a 1-year period.

Selecting the most appropriate dosage form, that ensures safe administration and adherence of medications, is a major issue for children. Marketed drugs, however, have rarely been tested for their use in children. There is a need for more data on drug formulations administered to children to identify unmet needs, and drive future paediatric research. We observed, over a 12-month follow-up, 117,665 oral drug administrations to 1998 hospitalized children. Nine-tenths belonged to five Anatomical Therapeutic Chemical classes: Alimentary tract & metabolism, Nervous system, Cardiovascular system, Anti-infectives for systemic use and Blood & blood forming organs, one third of drug doses administered to school-age children and adolescents were liquids, and extemporaneous capsules were commonly used in younger children. Our study shows that despite the advantages of solid dosage forms and recent evidence from randomized controlled trials showing their acceptability in infants, they are seldom used in paediatric practice.

[Type 1 xanthinuria: Report on three cases]. / Xanthinurie héréditaire de type 1 : à propos de trois cas.

Type 1 xanthinuria is a rare cause of urolithiasis due to xanthine dehydrogenase deficiency. Pediatric cases are exceptional. Through the genetic analysis of two cases, we discovered three mutations responsible for a loss of enzyme activity. The first one had a C.3536T>C missense mutation in the XDH gene and the other one was heterozygous for two mutations c.700+1G>T and c.31778_82delTCAT. We review the diagnostic methods, possible complications, and preventive measures for stone formation.

European Renal Best Practice Guideline on kidney donor and recipient evaluation and perioperative care

The European Best Practice Guideline group (EBPG) issued guidelines on the evaluation and selection of kidney donor and kidney transplant candidates, as well as post-transplant recipient care, in the year 2000 and 2002. The new European Renal Best Practice board decided in 2009 that these guidelines needed updating. In order to avoid duplication of efforts with kidney disease improving global outcomes, which published in 2009 clinical practice guidelines on the post-transplant care of kidney transplant recipients, we did not address these issues in the present guidelines.The guideline was developed following a rigorous methodological approach: (i) identification of clinical questions, (ii) prioritization of questions, (iii) systematic literature review and critical appraisal of available evidence and (iv) formulation of recommendations and grading according to Grades of Recommendation Assessment, Development, and Evaluation (GRADE). The strength of each recommendation is rated 1 or 2, with 1 being a 'We recommend' statement, and 2 being a 'We suggest' statement. In addition, each statement is assigned an overall grade for the quality of evidence: A (high), B (moderate), C (low) or D (very low). The guideline makes recommendations for the evaluation of the kidney transplant candidate as well as the potential deceased and living donor, the immunological work-up of kidney donors and recipients and perioperative recipient care.All together, the work group issued 112 statements. There were 51 (45%) recommendations graded '1', 18 (16%) were graded '2' and 43 (38%) statements were not graded. There were 0 (0%) recommendations graded '1A', 15 (13%) were '1B', 19 (17%) '1C' and 17 (15%) '1D'. None (0%) were graded '2A', 1 (0.9%) was '2B', 8 (7%) were '2C' and 9 (8%) '2D'. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research.We present here the complete recommendations about the evaluation of the kidney transplant candidate as well as the potential deceased and living donor, the immunological work-up of kidney donors and recipients and the perioperative recipient care. We hope that this document will help caregivers to improve the quality of care they deliver to patients. The full version with methods, rationale and references is published in Nephrol Dial Transplant (2013) 28: i1-i71; doi: 10.1093/ndt/gft218 and can be downloaded freely from http://www.oxfordjournals.org/our_journals/ndt/era_edta.html.

[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.

[Smith-Magenis syndrome is an association of behavioral and sleep/wake circadian rhythm disorders]. / Le syndrome de Smith-Magenis, une association unique de troubles du comportement et du cycle veille/sommeil.

Smith-Magenis syndrome (SMS) is a genetic disorder characterized by the association of facial dysmorphism, oral speech delay, as well as behavioral and sleep/wake circadian rhythm disorders. Most SMS cases (90%) are due to a 17p11.2 deletion encompassing the RAI1 gene; other cases stem from mutations of the RAI1 gene. Behavioral issues may include frequent outbursts, attention deficit/hyperactivity disorders, self-injuries with onychotillomania and polyembolokoilamania (insertion of objects into bodily orifices), etc. It is noteworthy that the longer the speech delay and the more severe the sleep disorders, the more severe the behavioral issues are. Typical sleep/wake circadian rhythm disorders associate excessive daytime sleepiness with nocturnal agitation. They are related to an inversion of the physiological melatonin secretion cycle. Yet, with an adapted therapeutic strategy, circadian rhythm disorders can radically improve. Usually an association of beta-blockers in the morning (stops daily melatonin secretion) and melatonin in the evening (mimics the evening deficient peak) is used. Once the sleep disorders are controlled, effective treatment of the remaining psychiatric features is needed. Unfortunately, as for many orphan diseases, objective guidelines have not been drawn up. However, efforts should be focused on improving communication skills. In the same vein, attention deficit/hyperactivity disorders, aggressiveness, and anxiety should be identified and specifically treated. This whole appropriate medical management is underpinned by the diagnosis of SMS. Diagnostic strategies include fluorescent in situ hybridization (FISH) or array comparative genomic hybridization (array CGH) when a microdeletion is sought and Sanger sequencing when a point mutation is suspected. Thus, the diagnosis of SMS can be made from a simple blood sample and should be questioned in subjects of any age presenting with an association of facial dysmorphism, speech delay with behavioral and sleep/wake circadian rhythm disorders, and other anomalies including short stature and mild dysmorphic features.

[Macrophage activation syndrome and autoimmunity due to visceral leishmaniasis]. / Syndrome d'activation macrophagique et auto-immunité cortico-sensible révélateurs d'une leishmaniose viscérale.

Hemophagocytic syndromes are a heterogeneous group of diseases characterized by an excessive immune response, mediated by activated cytotoxic T cells and macrophages. Among hemophagocytic syndromes, genetic and secondary forms can be distinguished. We report on the case of a male newborn who presented with macrophage activation syndrome associated with lymphoproliferation with favorable outcome under prednisone and cyclosporin. Hemopathy, infection, or genetic lymphohistiocytosis were initially ruled out. Severe autoimmunity was suspected because of positive antinuclear antibodies and Farr test associated with anemia and a positive Coombs test as well as cytolytic hepatitis with anti-liver, kidney microsome (LKM) antibodies. Treatment was therefore intensified by adding mycophenolate mofetil. This led to an unexpected deterioration of general health and lab exam results with recurrence of fever and inflammation. The initial investigations were revisited and completed by a liver biopsy, which revealed the presence of numerous leishmania parasites at the amastigote stage, enabling the diagnosis of visceral leishmaniasis. The patient's condition dramatically improved under liposomal amphotericin B treatment. Our observation shows that visceral leishmaniasis can present as lupus-like syndrome with lymphoproliferation. Moreover, the lack of leishmania on marrow aspiration cannot rule out the diagnosis of visceral leishmaniasis. Detection of leishmania by serological or molecular tests is mandatory in case of hepatosplenomegaly with hemophagocytic syndrome together with autoantibodies, in order to avoid useless and life-threatening exposure to immunosuppressive treatments.

[Relationship between glomerular filtration rate, uric acid, and parathyroid hormone in children]. / Relation entre débit de filtration glomérulaire, parathormone et acide urique chez l'enfant.

INTRODUCTION: Parathyroid hormone (PTH) and uric acid (UA) levels increase early during chronic kidney disease (CKD). The objective of this study was to evaluate the relationship between these two parameters at different stages of pediatric CKD. PATIENTS AND METHODS: One hundred patients (range, 5-18 years) were included in this retrospective study: they had undergone renal exploration with a direct measurement of the glomerular filtration rate (GFR) using the reference standard (i.e., inulin clearance, Cin) and presented with increased circulating levels of PTH and/or UA. RESULTS: GFR was normal in 39% of patients, with UA increased in 44% and PTH in 75% of them. Interestingly, 29% of the children with increased PTH levels had a strictly normal GFR (i.e., above 90 mL/min/1.73 m(2)). An inverse association was found between UA and GFR (r=-0.452, P ≤ 0.0001) as well as between PTH and GFR (r=-0.226, P=0.024). The same negative relationships were found between UA and PTH (r=-0.266, P=0.007), and between UA and the phosphate reabsorption rate (r=-0.415, P<0.001). DISCUSSION: Since hyperuricemia was found at all stages of CKD, an early silent tubular impairment can be discussed to explain these findings. The early increase in PTH levels during CKD has not been described by all authors, with North American studies describing rather late increased PTH levels during CKD. Prospective studies are required to confirm these data and evaluate the role of UA in the pathophysiology of the mineral disorders observed during CKD.

[Pediatric seizures and end-stage renal disease]. / État de mal convulsif révélateur d'une ostéodystrophie rénale.

Neonates and infants with hypocalcemia usually present with seizures, whereas this is less common in older children and teenagers. We report on a case of hypocalcemic seizures in a 16-year-old girl with undiagnosed end-stage renal disease with progressive growth retardation and bone deformations. We highlight the value of checking serum calcium, phosphate, and creatinine in children with growth retardation, seizures, and/or unexplained bone deformations. We also discuss the clinical consequences of pediatric renal osteodystrophy.

Comparison of cystatin C- and creatinine-based glomerular filtration rate formulas with inulin clearance in pediatric renal transplantation.

BACKGROUND: It has been suggested that plasma cystatin C (Cyst-C) concentrations provide better indicators of changes in glomerular filtration rate (GFR) than plasma creatinine concentration (PCr). METHODS: We compared the performance of five equations--2009 Schwartz, Local Schwartz, Larsson, Le Bricon, and Schwartz Combined--in 60 renal transplant children by calculating the mean bias, Pearson correlation coefficient (R) and determination (R2), 10% (P10) and 30% (P30) accuracies, and Bland-Altman plots. GFR was measured by inulin clearance. RESULTS: For the whole population, R2 was slightly lower for formulas based on Cyst-C or PCr, but the mean bias was lower, and P10 and P30 were greater, than using combined Schwartz equation. However, the mean estimated GFR by Schwartz 2009, Local Schwartz, and Schwartz combined equations was not statistically different from the mean inulin clearance measurement. CONCLUSIONS: In our pediatric transplant population, the combined Schwartz formula exhibited better performance to estimate GFR than formulae based on Cyst-C or combined PCr.

Dental abnormalities in Schimke immuno-osseous dysplasia.

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFß1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.

[Post-diarrheal haemolytic uremic syndrome: when shall we consider it? Which follow-up?]. / Syndrome hémolytique et urémique post-diarrhéique : Quand y penser ? Quel suivi ?

Haemolytic uremic syndrome (HUS) is characterized by thrombotic microangiopathy with acute renal failure, haemolytic anaemia with schizocytes and thrombocytopenia. Typical forms (D(+) HUS) are caused by gastrointestinal infection with Escherichia coli species producing verotoxines (or Shiga toxins, STEC). It is estimated that 5-8 % of infected individuals will develop HUS following STEC infection. E. coli O157:H7 is the most commonly involved serotype and can lead to D(+) HUS in 15 % of young infected children. Vehicles of STEC transmission are contaminated food (ground beef, unpasteurised dairy products, unwashed and uncooked fruit and vegetables), person-to-person transmission and contact with farm animals with STEC. After an average incubation period of 3 to 8 days, patients develop painful bloody diarrhoea followed by systemic toxinemia. This may lead to thrombotic microangiopathy with endothelial damage and activation of local thrombosis. Since 1996, the Institut de Veille Sanitaire (InVS) centralises all notified French cases of D(+) HUS in children less than 15 years of age and investigates cases regrouped by time and place for the presence of STEC risk factors. The average annual incidence ranges between 0.6 and one for 100 000 children younger than 15 years and with a peak at 1 year of age. Fifty-one percent of HUS occur between June and September. Patients with a suspicion of STEC infection or bloody diarrhoea should not receive antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs. Maintenance optimal hydration provides nephroprotection. The management of HUS remains supportive. Dialysis was required for 46 % of HUS cases in 2009. For similar indication, peritoneal dialysis has to be a first choice treatment. Neurological injury is the most frequent non-renal complication and the first cause of death. Early initiation of plasmapheresis might improve the prognosis. Overall mortality rate ranges between 1 and 5 %. One third of patients suffer from long-term renal morbidity such as proteinuria, arterial hypertension and decrease of glomerular filtration rate. The longer the duration of anuria, the greater the risk of sequellae. Any patient with a history of HUS needs a long-term renal follow-up.

[FGF23 and Klotho: the new cornerstones of phosphate/calcium metabolism]. / FGF23 et Klotho : les nouveaux incontournables du métabolisme phosphocalcique.

Since its first description as a phosphaturic agent in the early 2000s, fibroblast growth factor 23 (FGF23) has rapidly become the third key player of phosphate/calcium metabolism after PTH and vitamin D. FGF23 is a protein synthesized by osteocytes that acts mainly as a phosphaturic factor and a suppressor of 1α hydroxylase activity in the kidney. It inhibits the expression of type IIa and IIc sodium-phosphate cotransporters on the apical membrane of proximal tubular cells, thus leading to inhibition of phosphate reabsorption. Moreover, it also inhibits 1α hydroxylase activity. These two renal pathways account together for the hypophosphatemic effect of FGF23, but FGF23 has also been recently described as an inhibiting factor for PTH synthesis. Its exact role in bone remains to be defined. A transmembrane protein, Klotho, is an essential cofactor for FGF23 biological activity, but it can also act by itself for calcium and PTH regulation. This paper gives an overview of these recent data of phosphate/calcium physiology, as well as a description of clinical conditions associated with FGF23 deregulation (genetic diseases and chronic kidney disease). As a conclusion, future therapeutic consequences of the FGF23/Klotho axis are discussed.