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Primary hyperoxalurias are rare recessive inherited inborn errors of glyoxylate metabolism. They are responsible for progressive renal involvement, which further lead to systemic oxalate deposition, which can even occur in infants. Primary hyperoxaluria type 1 is the most common form in Europe and is due to alanine-glyoxylate aminostransferase deficiency, a hepatic peroxisomal pyridoxin-dependent enzyme. Therefore primary hyperoxaluria type 1 is responsible for hyperoxaluria leading to aggressive stone formation and nephrocalcinosis. As glomerular filtration rate decreases, systemic oxalate storage occurs throughout all the body, and mainly in the skeleton. The diagnosis is first based on urine oxalate measurement, then on genotyping, which may also allow prenatal diagnosis to be proposed. Conservative measures - including hydration, crystallization inhibitors and pyridoxine - are safe and may allow long lasting renal survival, provided it is given as soon as the diagnosis has been even suspected. No dialysis procedure can remove enough oxalate to compensate oxalate overproduction from the sick liver, therefore a combined liver and kidney transplantation should be planned before advanced renal disease has occurred, in order to limit/avoid systemic oxalate deposition. In the future, primary hyperoxaluria type 1 may benefit from hepatocyte transplantation, chaperone molecules, etc.

Systemic lupus erythematosus (SLE) is a rare autoimmune disease, which is more severe in case of pediatric onset. This may be due to greater involvement of genetic factors in comparison to adult forms. SLE is a multifactorial disease and is thought to be secondary to a combination of genetic, environmental factors as well as immunological defects. Studies on early-onset SLE and both familial and syndromic cases have led to the discovery of monogenic form of SLE, with autosomal or recessive inheritance. Related genes are responsible for complement deficiency and excessive production of interferon-alpha, both mechanisms studied in SLE pathogenesis. Apoptosis defect described in autoimmunity and lymphoproliferation syndromes is the human counterpart of lpr/lpr mouse model, deeply investigated as a murine SLE model. In this review, we discuss all monogenic Mendelian forms of SLE and underline the impact of this gene discovery on better understanding of SLE pathogenesis.

Steroid-resistant focal segmental glomerulosclerosis (FSGS) often recurs after renal transplantation. In this international survey, we sought to identify genotype-phenotype correlations of recurrent FSGS. We surveyed 83 patients with childhood-onset primary FSGS who received at least one renal allograft and analyzed 53 of these patients for NPHS2 mutations. The mean age at diagnosis was 6.7 years, and the mean age at first renal transplantation was 13 years. FSGS recurred in 30 patients (36%) after a median of 13 days (range, 1.5 to 152 days). Twenty-three patients received a second kidney transplant, and FSGS recurred in 11 (48%) after a median of 16 days (range, 2.7 to 66 days). None of the 11 patients with homozygous or compound heterozygous NPHS2 mutations developed recurrent FSGS compared with 45% of patients without mutations. These data suggest that genetic testing for pathogenic mutations may be important for prognosis and treatment of FSGS both before and after transplantation.

Primary hyperoxaluria (PH) is a rare genetic disease, in which high urinary oxalate (Uox) cause recurrent kidney stones and/or progressive nephrocalcinosis, often followed by early end-stage renal disease, as well as extremely high plasma oxalate, systemic oxalosis and premature death. Oxalobacter formigenes, an anaerobic oxalate degrading bacterium, naturally colonizes the colon of most humans. Orally administered O. formigenes (Oxabact) was found to significantly reduce urine and plasma oxalate. We aimed to evaluate its effect and safety in a randomized, double-blind, placebo-controlled multicenter study. Oral Oxabact was given to PH patients (>5 years old, Uox > 1.0 mmol/1.73 m(2)/day, glomerular filtration rate (GFR) > 50 mL/min) at nine PH referral sites worldwide. Primary endpoint was the change from baseline in Uox (mmol/1.73 m(2)/day) after 24 weeks of treatment (>20% reduction). Of the 43 subjects randomized, 42 patients received either placebo (23 subjects) or Oxabact (19 subjects). The change in Uox was 160 mmol/mol, Oxabact -28%, placebo -6%; P < 0.082). No serious adverse events were reported. Oxabact was safe and well tolerated. However, as no significant change in Uox was seen, further studies to evaluate the efficacy of Oxabact treatment are needed

Primary hyperoxaluria type 1 (PH1) is a rare recessive autosomal inborn error of glyoxylate metabolism leading to oxalate retention, the first target of which is the kidney. The disease is caused by a defect of the liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase. Patients with pyridoxine-resistant forms of PH1 usually require organ replacement therapy, i.e. liver transplantation to supply the deficient enzyme and/or kidney transplantation to replace the affected organ. The current experience of the management of Ph1 has emphasized two main points: (1) end-stage renal failure must be avoided since it increases dramatically the risk of systemic involvement, (2) the correction of oxalate overproduction and organ overload requires the removal of the host liver. Practical attitudes towards these ideas are difficult to assess and an individualized strategy is therefore required. Isolated kidney transplantation should be limited to adult patients with late-onset and a mild course of the disease. The present experience of combined liver-kidney transplantation was gained mainly in adult patients with severe systemic involvement; the 3-year patient survival rate recently increased to 82%. This figure might be improved if the procedure were performed earlier while the glomerular filtration rate (GFR) is above 25 ml/min per 1.73 m2. Isolated liver transplantation should be considered in carefully selected children with severe forms of pyridoxineresistance (PH1) before GFR has dropped to less than 30 ml/min per 1.73 m2; it seems to be indicated especially in the presence of a rapid decline of GFR in the preceding year. In two young children who underwent isolated liver transplantation in our units 4 years ago, renal function could be stabilized and severe extrarenal involvement prevented.

This letter discusses therapeutic disparities between developing countries and developed countries for patients with nephropathic cystinosis, one of a number of rare diseases for which therapy exists but is unevenly distributed.

Summary Background and objectives Estimation of GFR in children is challenging; reference methods are cumbersome, and formulas have limitations. The aims of this study were to evaluate (1) the new creatinine-based formula recently proposed by Schwartz using a kinetic colorimetric compensated Jaffe technique; (2) some cystatin C-derived formulas (Hoek, Le Bricon, Larsson, Rule, Filler, and Zappitelli) using a nephelemetric technique; and (3) combined formulas using both cystatin and creatinine (Zappitelli and Bouvet). Design, setting, participants, & measurements These formulas were evaluated in a cross-sectional cohort of 252 children with moderate CKD or normal GFR, in comparison with the reference standard (inulin clearance, iGFR). Mean age, body weight, height, creatinine, and cystatin C were 10.7 ± 4.0 years, 35 ± 15 kg, 137 ± 20 cm, 55 ± 30 μmol/L, and 0.91 ± 0.35 mg/L, respectively. Results Mean ± SD iGFR was 101 ± 32 ml/min per 1.73 m2. When evaluating agreement between these formulas and iGFR (e.g. correlation, Bland Altman plots, bias, and accuracies), there was a good correlation between iGFR and all Le Bricon, Larsson, Rule, and Zappitelli (both) and locally adapted Schwartz and 2009 Schwartz formulas; by contrast, Filler and original 1976 Schwartz formulas overestimated iGFR, whereas Hoek and Bouvet formulas underestimated iGFR. Conclusion Different cystatin C-derived formulas (at least Larsson and Le Bricon) for estimating GFR as well as the Zappitelli combined formula are accurate in addition to the new Schwartz bedside formula in a general pediatric population.

Primary hyperoxaluria type 1, the most common form of primary hyperoxaluria, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. This results in increased synthesis and subsequent urinary excretion of the metabolic end-product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. As glomerular filtration rate decreases due to progressive renal involvement, oxalate accumulates and results in systemic oxalosis.Diagnosis is still often delayed. It is mainly established on the basis of clinical and sonographic findings, urinary oxalate ± glycolate assessment, and DNA analysis.Following specific conservative measures, the ultimate management is based on organ transplantation. Correction of the enzyme defect by liver transplantation should be planned before systemic oxalosis develops to optimize outcomes and may be either simultaneous (immunological benefit) or sequential (biochemical benefit) liver-kidney transplantation depending on disease staging, facilities, and access to deceased or living donors. Allograft and patient survival currently approaches that of transplant patients with kidney transplantation alone and with other diseases requiring combined liver-kidney transplantation. In addition, this strategy has also provided significant improvement in both quality of life and statural growth.

International audience; Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2 which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. While truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

Background. It has been demonstrated that alkylating agents such as cyclophosphamide (CYP) are effective in reducing the risk of relapse in frequently relapsing (FRNS) and steroid-dependent nephrotic syndrome (SDNS). Little is known about prognostic factors in SDNS and FRNS treated by CYP. The objectives of this study are to determine long-term outcomes and factors associated with sustained remission in these patients. Methods. We retrospectively studied the data from 143 children (104 boys) with SDNS and FRNS treated with CYP in six centres over 15 years. Relapse-free survival was estimated by Kaplan–Meier method. The determinants of long-term remission were assessed by univariate and multivariate analyses using Cox proportional hazard models. Results. Median age at diagnosis was 3.7 years (interquartile range: IQR 2.3–5.9), and median follow-up was 7.8 years (IQR 4.0–11.8). CYP treatment was introduced after a median time of 1.7 years (IQR 0.7–5.9) after diagnosis. Patients received a median cumulative dose of 168 mg/kg (IQR 157–197) body weight. Relapse-free survival was 65%, 44%, 27% and 13% after 6 months, 1 year, 2 years and 5 years, respectively. In multivariate analysis, sustained remission >2 years was associated with age at treatment >5 years (P = 0.02) and cumulative dose of CYP >170 mg/kg (P = 0.02). Frequently relapsing versus steroid-dependent status and female gender were predictors of borderline significance. Height and body mass index standard deviation score were significantly influenced by CYP treatment. Conclusion.In our study, long-term efficacy of cyclophosphamide in steroid-responsive nephrotic syndrome is disappointing. Further well-designed trials are required to evaluate the efficacy of other steroid-sparing agents. NEPHROLOGY DIALYSIS TRANSPLANTATION, ISSN : 0931-0509, DOI : 10.1093/ndt/gfq405, Issue :1, Volume : 26, pp. 178–184, 2011. ; ; ; steroids

FS is an inherited disease characterized by male pseudohermaphroditism and glomerular involvement leading to end-stage renal disease during adolescence or early adulthood (J Pediatr 1964:64:740). The FS phenotype in 46,XY patients consists of female external genitalia, gonadal dysgenesis, high risk of gonadoblastoma, and development of renal failure in the second decade of life. FS is caused by heterozygous mutation in intron 9 of the WT1 leading to a change in splicing that results in loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/-KTS isoforms that is critical for proper gonadal and renal development (Nat Genet 1997:17:467; Hum Mol Genet 1998:7:709). We report on a patient followed for FS revealed by acute peritoneal syndrome because of ovarian dysgerminoma. Therapeutic options had led to an unusual course with recurrent neoplastic disease after renal transplantation.

The objective was to develop a population pharmacokinetic pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine-MMF-treated patients was 33% higher than in tacrolimus-MMF-treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic-pharmaco-genetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal-transplant patients.

A 7-year-old girl with membranous nephropathy is reported who suffered 16 months later from an orbital rhabdomyosarcoma. Proteinuria disappeared at the time of the remission of the tumor. Membranous nephropathy as paraneoplastic syndrome is exceptional in children, since only two other cases associated with a solid tumor have been reported in the literature.

Achieving normal height in children after renal transplantation is a crucial issue for both quality of life and self-esteem. The management of growth retardation in renal transplant recipients includes adequate nutritional intake, correction of acidosis, optimal drug compliance, limited calcineurin inhibitor nephrotoxicity, steroid-sparing strategies, and sometimes recombinant human growth hormone.

Background Cancer is a well-recognized complication of organ transplantation. The pattern of malignancies that occur in the paediatric graft population is different from that in the general paediatric population and in the population of adult organ transplant recipients. Methods We reviewed medical records from 240 consecutive paediatric renal transplantations performed in 219 children, aged less than 19 years, in our centre between April 1987 and March 2007. Data from patients who had been transferred into adult units were extracted from the French registries of dialysis and transplantation. Results Among the 219 children who underwent renal transplantation during the study period, 16 (7.3%) developed malignancy. The cumulative incidence of cancer was 1.9, 4.0, 6.9 and 10.2% at 1, 5, 10 and 15 years post-transplantation, respectively. The 10-year incidence of post-transplantation lymphoproliferative disorder (PTLD) was 4.5%. Other identified cancers were Hodgkin lymphoma, Burkitt lymphomas, renal papillary carcinoma, thyroid papillary carcinoma, recurrent ovarian seminoma and skin cancer. The mortality rate was 25% (4/16). Conclusion Early detection of cancer in transplant recipients is of great importance. Regular screening for persistent Epstein-Barr virus (EBV) DNA viral load in patients at risk for developing PTLD is recommended. The occurrence of skin cancer in transplanted children is extremely rare during childhood, but cases can develop in early adulthood.

Several drugs and other compounds can induce acute and/or chronic nephrotoxicity. The goal of this study was to review clinical features of nephrotoxicity induced by ‘atypical’ or ‘unconventional’ agents, such as environmental agents (metals, minerals, animals), food agents (mushrooms, aristolochic acid, medicinal traditional herbals, dietary supplements, melamine), drugs, and other products (ethylene glycol). Nephrotoxicity varies according to local background, dependent on different food and cultural customs, as well as to differences in local fauna and flora. The incidence of such a phenomenon is not well known. Many different pathophysiological pathways are involved, and the spectrum of renal lesions is rather wide. ‘Epidemic nephrotoxicity’ may occur, as recently illustrated by the melamine epidemics in Chinese infants receiving powdered milk formulas; a rapid reaction to unusual increased frequency of acute kidney injury and nephrolithiasis in young children has led to a rapid analysis from international experts, with subsequent recommendations for diagnosis and care. Nephrotoxicity should be considered when there is any unexplained renal impairment, especially in children.

Resume Objectif Evaluer la faisabilite d’un mode de recueil systematique et actif des evenements indesirables medicamenteux (EIM) chez les enfants aux urgences pediatriques. Population et methodes Il s’agit d’une etude d’observation prospective avec un recueil systematique et actif des EIM potentiels declares par les medecins, sollicites par la presence d’un pharmacologue ou d’un membre du centre regional de pharmacovigilance (CRPV) de Lyon, sur une periode de 6 mois consecutifs de mars a septembre 2005 aux urgences pediatriques de l’hopital Edouard-Herriot (Lyon). Tous les enfants de moins de 18 ans presentant un EIM a l’origine d’une consultation aux urgences pediatriques ont ete inclus. Resultat Au cours de la periode d’etude, 90 EIM « potentiels » ont ete declares, dont 43 valides par le CRPV. Trente-quatre patients etaient âges de moins de 5 ans (79 %). Quatorze EIM ont ete juges graves dont 3 ont mis en jeu le pronostic vital : reaction anaphylactique apres injection d’amoxicilline, etat de mal convulsif severe suite a une erreur de medicament pour une prophylaxie antipaludeenne, convulsion avec perte de connaissance suite a une vaccination ROR et hepatite B. Trois EIM ont ete juges evitables. Les antibiotiques et les vaccins etaient les principaux responsables des EIM (76 %). Une reaction cutanee et la fievre etaient les manifestations cliniques les plus frequentes (35 cas). Le mode de recueil actif a permis de doubler le nombre de cas d’EIM valides par rapport a celui obtenu de facon spontanee sur une periode de temps equivalente l’annee precedant cette etude ( n = 43 vs n = 17, p Conclusion Un mode de recueil actif, avec interaction etroite entre pharmacologues responsables de pharmacovigilance et cliniciens est necessaire et faisable et a permis de mieux quantifier et qualifier les EIM survenant chez les enfants. Un systeme de declaration simplifie et informatise est a etudier.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome was retrospectively studied in 78 children in eight centers for the past 20 years. Median age at onset was 4.4 years (1.1-15.0 years) and the gender ratio was 1.4. Median follow-up period was 7.7 years (1.0-19.7 years). The disease in 45 patients (58%) was initially not steroid-responsive and in 33 (42%) it was later non-responsive. The main therapeutic strategies included administration of ciclosporine (CsA) alone (n = 29; 37%) and CsA + mycophenolate mofetil (n = 18; 23%). Actuarial patient survival rate after 15 years was 97%. Renal survival rate after 5 years, 10 years and 15 years was 75%, 58% and 53%, respectively. An age at onset of nephrotic syndrome (NS) > 10 years was the only independent predictor of end-stage renal disease (ESRD) in a multivariate analysis using a Cox regression model (P < 0.001). Twenty patients (26%) received transplants; ten showed recurrence of the NS: seven within 2 days, one within 2 weeks, and two within 3-5 months. Seven patients lost their grafts, four from recurrence. Owing to better management, kidney survival in idiopathic steroid-resistant nephrotic syndrome (SRNS) has improved during the past 20 years. Further prospective controlled trials will delineate the potential benefit of new immunosuppressive treatment.

A single-center prospective cohort study was designed to identify alterations of renal function during childhood in children born prematurely. A cohort of 143 such babies born over a 4-year period (birth weight less than 1000 g and/or less than 30 weeks of gestation) was prospectively included at birth. A mailing was sent to all parents to propose renal evaluation. Among the 50 included children, 23 had intra-uterine and 16 had extrauterine growth retardation. When comparing both of these groups to 11 children with appropriate pre- and postnatal growth at a mean follow-up of 7.6 years, both groups of growth-restricted children had slightly but significantly lower glomerular filtration rates, measured by inulin clearance, although both groups were still within the normal range for their ages. There were no differences for other renal parameters, neonatal therapies or complications, except for postnatal corticosteroid exposure. Children with extrauterine growth restriction were found to have significantly lower protein-energy intake during their first week of life than the intrauterine growth-restricted or the normotrophic children. Our study found that children with either intra- or extrauterine growth retardation are at risk of decreased glomerular filtration rates during childhood. Extrauterine growth restriction represents a new risk factor for long-term renal impairment in premature children.

Background Ante/neonatal Bartter syndrome (BS) is a hereditary salt-losing tubulopathy due to mutations in genes encoding proteins involved in NaCl reabsorption in the thick ascending limb of Henle's loop. Our aim was to study the frequency, clinical characteristics and outcome of each genetic subtype. Methods Charts of 42 children with mutations in KCNJ1 (n = 19), SLC12A1 (n = 13) CLCNKB (n = 6) or BSND (n = 4) were retrospectively analysed. The median follow-up was 8.3 [0.4-18.0] years. Results We describe 24 new mutations: 10 in KCNJ1, 11 in SLC12A1 and 3 in CLCNKB. The onset of polyhydramnios, birth term, height and weight were similar for all groups; three patients had no history of polyhydramnios or premature birth and had CLCNKB mutations according to a less severe renal sodium wasting. Contrasting with these data, patients with CLCNKB had the lowest potassium (P = 0.006 versus KCNJ1 and P = 0.034 versus SLC12A1) and chloride plasma concentrations (P = 0.039 versus KCNJ1 and P = 0.024 versus SLC12A1) and the highest bicarbonataemia (P = 0.026 versus KCNJ1 and P = 0.014 versus SLC12A1). Deafness at diagnosis was constant in patients with BSND mutations; transient neonatal hyperkalaemia was present in two-thirds of the children with KCNJ1 mutations. Nephrocalcinosis was constant in KCNJ1 and SLC12A1 but not in BSND and CLCNKB patients. In most cases, water/electrolyte supplementation + indomethacin led to catch-up growth. Three patients developed chronic renal failure: one with KCNJ1 mutations during the second decade of age and two with CLCNKB and BSND mutations and without nephrocalcinosis during the first year of life. Conclusions We confirmed in a large cohort of ante/ neonatal BS that deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. Chronic renal failure is a rare event, associated in this cohort with three genotypes and not always associated with nephrocalcinosis.

Human herpesvirus 6 (HHV-6) infection can induce unusual complications in transplant patients, such as interstitial pneumonitis, encephalitis and marrow aplasia. We describe the clinical course of HHV-6 infection in a girl with renal transplantation. She presented with diarrhea and poor feeding on day 36 post-transplantation (Tx), after a 5-day steroid pulse for clinical signs of acute rejection. A week later she developed fever and had elevated plasma creatinine and lactic dehydrogenase levels, but a physical examination did not reveal any anomalies with respect to suggest rash, pneumonitis, encephalitis or lymphadenopathy. Two weeks later, the patient developed anemia and leucopenia. HHV-6 was the only pathogen detected by the PCR assay of the serum and marrow aspiration. The patient had a successful recovery without specific treatment. This case report highlights the wide spectrum of complications resulting from HHV-6 infection in immunosuppressed patients.

15th Paediatric Rheumatology European Society (PreS) Congress Wietse Kuis, Patricia Woo, Angelo Ravelli, Hermann Girschick, Michael Hofer, Johannes Roth, Rotraud K Saurenmann, Alberto Martini, Pavla Dolezova, Janjaap van der Net, Pierre Quartier, Lucy Wedderburn and Jan Scott Meeting abstracts – A single PDF containing all abstracts in this Supplement is available here .

Uric acid may be involved in the development and progression of kidney diseases. Hyperuricemia is a common feature in adult liver transplant recipients but there is limited information in children. In order to estimate the incidence, predictors of hyperuricemia in pediatric liver transplant recipients, and to assess whether hyperuricemia may impact long-term renal function determined by measured GFR, we reviewed data of 70 children who received a first liver transplant between 1991 and 2005 (median follow-up 7.1 yr). Renal function tests performed annually included uric acid concentration, inulin and uric acid clearances. The cumulative incidence of hyperuricemia was 32% at 10-yr post-transplantation, mainly because of decreased urate excretion. The only factor significantly associated with an increased risk of hyperuricemia was older age. After adjustment for donor and recipient age, gender, primary liver disease, immunosuppression, and post-operative acute renal failure, hyperuricemia as time dependent variable tended to predict (p = 0.05) subsequent CRI. The control of serum urate concentration in eight of the 21 hyperuricemic patients either by nutritional management or by allopurinol was not followed by a significant GFR improvement. Hyperuricemia after liver transplantation in children is a frequent problem which needs further investigation.

Although medical guidelines generally are graded according to their evidence level, low evidence 'judgement' are generally perceived as much as absolute truth by the medical community as high evidence 'guidelines' are. Being aware of this bias, a workgroup appointed by the European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA), the members of which are the authors of the current publication, decided that European nephrology guidelines issued by the Association should be published only as 'guidelines' in the case of high-level evidence; otherwise they should be named 'recommendations' or 'position statements' and be published in a different format. Acknowledging that in nephrology, high levels of evidence are often lacking, it was also decided to rename the responsible body from European Best Practice Guidelines (EBPG) to European Renal Best Practice (ERBP). The present publication reviews the arguments based on which this decision was taken.

Hypersensitivity to inulin (polyfructan) is a rare event; two cases of food allergy and some patients presenting with allergy and hypersensitivity after inulin infusion have been reported. An 11-year-old boy suffering from severe immunoglobulin (Ig)A nephropathy (IgAN) experienced both anaphylactic reaction and concomitant relapse of his nephropathy following inulin infusion, used for measuring glomerular filtration rate (GFR) 2 years after the appearance of his initial symptoms. Pruritus, wheezing and cough were observed during a first renal function test; results of prick and intradermal tests were negative for inulin. The patient presented with pallor, asthenia and oliguria when a second inulin infusion was performed under dexchlorpheniramine, leading to the immediate cessation of the infusion. He was readmitted 2 days later because of fatigue and nausea related to acute renal failure. A drug-induced acute interstitial nephritis was first suspected. However, due to the presence of macroscopic haematuria and proteinuria, a renal biopsy was performed and showed acute proliferative relapse of IgAN. The underlying mechanism of inulin hypersensitivity is not well known. We can hypothesize that inulin had activated the innate immune system. Inulin may, thus, have been the initiating event of the renal relapse, acting like an infection, in a patient with IgA-mediated immunological dysregulation.

BACKGROUND: Type 1 pseudohypoaldosteronism (PHA1) is a salt-wasting syndrome caused by mineralocorticoid resistance. Autosomal recessive and dominant hereditary forms are caused by Epithelial Na Channel and Mineralocorticoid Receptor mutation respectively, while secondary PHA1 is usually associated with urological problems. METHODS: Ten patients were studied in four French pediatric units in order to characterize PHA1 spectrum in infants. Patients were selected by chart review. Genetic, clinical and biochemistry data were collected and analyzed. RESULTS: Autosomal recessive PHA1 (n = 3) was diagnosed at 6 and 7 days of life in three patients presenting with severe hyperkalaemia and weight loss. After 8 months, 3 and 5 years on follow-up, neurological development and longitudinal growth was normal with high sodium supplementation. Autosomal dominant PHA1 (n = 4) was revealed at 15, 19, 22 and 30 days of life because of failure to thrive. At 8 months, 3 and 21 years of age, longitudinal growth was normal in three patients who were given salt supplementation; no significant catch-up growth was obtained in the last patient at 20 months of age. Secondary PHA1 (n = 3) was diagnosed at 11, 26 days and 5 months of life concomitantly with acute pyelonephritis in three children with either renal hypoplasia, urinary duplication or bilateral megaureter. The outcome was favourable and salt supplementation was discontinued after 3, 11 and 13 months. CONCLUSIONS: PHA1 should be suspected in case of severe hyperkalemia and weight loss in infants and need careful management. Pathogenesis of secondary PHA1 is still challenging and further studies are mandatory to highlight the link between infection, developing urinary tract and pseudohypoaldosteronism.

BACKGROUND: Basiliximab, a monoclonal CD25 antibody has proofed effective in reducing acute rejection episodes in adults in various immunosuppressive regimens. The effect of basiliximab in the pediatric population is controversial. METHODS: In a 12-month, double-blind, placebo-controlled trial, renal transplant patients aged 1 to 18 years were randomized to basiliximab or placebo with cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids. The intent-to-treat population comprised 192 patients (100 basiliximab and 92 placebo). RESULTS: The primary efficacy endpoint, time to first biopsy-proven acute rejection episode, or treatment failure by month 6, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo-treated patients (Kaplan-Meier estimates; hazard ratio 0.72, two-sided 90% confidence interval 0.416-1.26, n.s.). The rate and severity of subclinical rejections in protocol biopsies performed at 6 months posttransplant was higher in the basiliximab group (25.0%) than in the placebo group (11.7%). Patient and death-censored graft survival at 12 months was 97% and 99%, respectively, in the basiliximab cohort, and 100% and 99% among placebo-treated patients (n.s.). Renal function was similar in both treatment groups, and there were no significant between-treatment differences in the incidence of adverse events or infections. CONCLUSIONS: Addition of basiliximab induction to a regimen of cyclosporine microemulsion, mycophenolate mofetil, and steroids resulted in a numerically lower but not significant incidence of biopsy-proven acute rejection versus placebo and excellent graft and patient survival at 1 year in pediatric renal transplant recipients. Whether this numerical difference is a true therapeutic benefit in view of the higher rate and severity of subclinical rejections in the basiliximab group in the protocol biopsy will be investigated in a long-term follow-up study.

The bone mineral density (BMD) of the lumbar spine (L1-L4) was measured by dual energy x-ray absorptiometry (Hologic QDR 1000) in 135 healthy caucasian children, aged 1-15 yr, and values were correlated with age, height, weight, body surface, bone age, pubertal status, calcium intake, vitamin D supplementation, and serum bone gla protein. BMD increased with age in children of both sexes (r = 0.88; P less than 0.001) from 0.446 +/- 0.048 g/cm2 at 1 yr to 0.625 +/- 0.068 g/cm2 at 10 yr and 0.891 +/- 0.123 g/cm2 at 15 yr of age. The increase was steeper at the time of puberty, reaching values above 0.80 g/cm2 after puberty was achieved. There were no significant differences between boys and girls, except at the age of 12 yr when BMD was higher in girls than in boys (P = 0.007), probably because of the earlier onset of puberty in females. BMD was also highly correlated with height, weight, body surface, and bone age. BMD was not correlated with calcium intake when age was held constant, nor with vitamin D supplementation. Serum bone gla protein showed a steady increase during childhood, with peak values at 11-12 yr of age, and was weakly but significantly correlated with BMD (r = 0.27; P = 0.007). Because of low irradiation exposure, rapid scanning, and high precision, dual energy x-ray absorptiometry is a noninvasive method which is well adapted to the child. It should be helpful in the investigation and follow-up of children with diseases impairing bone metabolism.

Living-donor transplantation has several obvious advantages for children: better graft-survival than cadaveric-transplantation, the possibility to be pre-emptive and avoid dialysis and its burden to the child, to be programmed during school holidays. However, its negative aspects must not be ignored. They are mainly psychological and concern the adolescent. The affective burden of both living-donation and transplantation is so strong that a psychological check-up is mandatory for the donor but also for the recipient and even the non-donor parent. In the medical evaluation of the donor, specific explorations, such as the search of a genetic mutation, could be necessary in the case of hereditary renal disease.

The etiologies of early onset nephrocalcinosis in consanguineous families include five major inherited recessive disorders: primary hyperoxaluria (PH), familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), distal renal tubular acidosis (dRTA), hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and antenatal Bartter syndrome. In this paper, we describe two girls from consanguineous parents with early onset nephrocalcinosis. Based on both clinical and biochemical assessment in combination with molecular genetics, we have shown that the etiology of nephrocalcinosis is different in each girl: one had FHHNC and her sister had dRTA.

Fabry disease is a rare X-linked lysosomal storage disease leading to systemic involvement, mainly through GL-3 endothelial deposition. Initial symptoms may occur during childhood (acroparesthesia, angiokeratoma), prior to adulthood complications, i.e. renal, ocular, cerebral, neurological and cardiovascular involvement. An early diagnosis of the disease may be challenging because of a frequent atypical clinical presentation. Indeed, independent of conservative treatment (pain, proteinuria, chronic renal failure, arterial hypertension, heart failure, etc), enzyme therapy using recombinant alpha-galactosidase (agalsidase) has provided a safe pathophysiological approach, leading to significant organ functional improvement (mainly kidney and heart) and improved quality of life, which parallels tissue GL-3 clearance. Such a treatment is safe and efficient but its biweekly intravenous administration is still uncomfortable, so that further alternative therapeutic approaches may be encouraged.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiplayseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Renal tubular dysgenesis (RTD) is a clinical disorder either acquired during fetal development or inherited as an autosomal recessive condition. Inherited RTD is caused by mutations in the genes encoding the components of the renin-angiotensin system angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II receptor type 1. Inherited RTD is characterized by early onset oligohydramnios, skull ossification defects, preterm birth and neonatal pulmonary and renal failure. The histological hallmark is the absence or poor development of proximal tubules. So far, all patients died either in utero or shortly after birth. We report the first patients with inherited RTD surviving the neonatal period and still being alive. Genetic and functional analysis of the renin-angiotensin system contributes to the diagnosis of RTD. In conclusion, the clinical diagnosis of inherited RTD is easily missed after birth without renal biopsy or information on affected family members. Genetic and functional analysis of the renin-angiotensin system contributes to correct diagnosis.

Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.

We report on a case of hepatitis B virus-related polyarteritis nodosa (PAN) in a 4-year-old Turkish boy who was first admitted because of severe arterial hypertension. The diagnosis of PAN was provided by conventional renal arteriography and the child was successfully treated with intensive sequential therapy combining short-term prednisone, plasma exchange and interferon-alpha-2b. Nine years later, he had no sign of PAN, normal blood pressure and normal renal function in the absence of any treatment.

BACKGROUND: In a previous article, we studied decisions to withhold or withdraw life-sustaining treatment (LST) taken between 1995 and 2001 in 31 French-speaking paediatric nephrology centres. Files were available for 18 of the 31 centres. A grid was used to analyse the criteria on which decisions were based, and the results were enriched by an analysis of interviews with the doctors at these centres (31 interviews with doctors from the 18 centres). The goal was to describe in detail and to specify the criteria on which decisions to withhold or withdraw LST were based, in cases extracted from the files. The second paper deals exclusively with the interviews with doctors and analyses their lifetime's experience and perception. METHODS: We carried out semi-directed interviews with nephrologists from all the paediatric nephrology centres in France and the French-speaking regions of Switzerland and Belgium. RESULTS: We interviewed 46 paediatric nephrologists. Most were aware that decisions relating to LST are necessary and based on the assessment of the child's quality of life. According to them, decisions are not based on scientific criteria, but on the capacity to accept handicap, the family's past experiences and the doctor's own projections. They report that their task is particularly difficult when their action may contribute to death (withdrawal of treatment or acceleration of the process). They feel that their duty is to help the families in the acceptance of the doctors' decision rather than to encourage their participation in the decision-making process (DMP). CONCLUSIONS: This article shows that paediatric nephrologists differ in their opinions, mostly due to their own ethical convictions. This observation highlights the need to establish common rules taking into account the views held by doctors. This is the only way to establish an ethical code shared by professionals.

To outline the specific oral surveillance needs of renal transplant children, we report the 4-year follow-up data of 106 children examined routinely on a 6-month basis and upon request from the medical team or the parents in the interval. Data were recorded for hard and soft dental tissues, including enamel defects carious lesions, gingival status, orthodontic treatment needs, and wisdom teeth eruption. Hard-tissue lesions were noted in 34.9% of the children, caries lesions on the permanent teeth were seen in 15.0% of cases, 18.86% of the patients had orthodontic treatment. Spontaneous examination, upon request for medical reasons, was given for 26 children. Twenty-one demands originated from the parents. Over a 4-year period the attendance of a dental specialist resulted in a significant improvement in the oral health of the renal transplant children.

Congenital or acquired disorders of patency of the inferior vena cava (IVC) or iliac veins have been considered for a long time to be an almost insurmountable technical obstacle in paediatric renal transplantation. The authors report their experience based on 7 transplantations performed in children with a disorder of venous patency, in whom renal transplantation was able to be performed. More generally, they also discuss the available technical options based on a review of the literature.From April 1987 to January 2002, renal transplantation was performed in 7 children with congenital or acquired abnormality of the iliac veins or IVC in our unit. All children underwent radiological assessment by venous Doppler ultrasound before transplantation. The contribution of radiological examinations to the diagnosis, the surgical technique performed, postoperative complications, patient survival and graft survival as well as long-term renal function were studied retrospectively.Four of the 7 transplanted children presented a congenital anomaly of the IVC and 3 had acquired thrombosis. In 5 out of 7 cases, the diagnosis was established before transplantation by Doppler ultrasound (completed by cavography in one case). The transplant renal vein was anastomosed to the iliocaval system in the majority of cases and the portal system had to be used in one case. With a mean follow-up of 94 months, all children have a functioning graft with a mean serum creatinine of 88 micromol/l.Disorders of patency of the IVC or iliac veins in children waiting for renal transplantation are rare, but these abnormalities can cause problems for the surgical team and compromise graft survival. Radiological assessment of patency of the venous network must help to demonstrated these abnormalities in order to optimally adapt the transplantation technique, which ensures very acceptable graft survival rates.