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International audience; Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

This position statement brings up guidance on pre-emptive kidney transplantation from living donors. The provided guid- ance is based on a systematic review of the literature.

International audience; BACKGROUND: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. OBJECTIVE: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. METHODS: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. RESULTS: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T~cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in~vitro. The latter defect correlated in~vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1~had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. CONCLUSION: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

To determine the prevalence of microalbuminuria and associated factors among Congolese human immunodeficiency virus (HIV)-infected children.This was a cross-sectional study in which 77 HIV-infected antiretroviral therapy-naive children and 89 uninfected controls were enrolled. Microalbuminuria was assessed using the immune-turbidimetry method, and associated factors were studied by logistic regression.The prevalence of microalbuminuria was 18% in the HIV-infected children and 2% in the HIV-uninfected children. No common determinants of proteinuria were significantly associated with microalbuminuria.

Background Estimating kidney glomerular filtration rate (GFR) is of utmost importance in many clinical conditions. However, very few studies have evaluated the performance of GFR estimating equations over all ages and degrees of kidney impairment. We evaluated the reliability of two major equations for GFR estimation, the CKD-EPI and Schwartz equations, with urinary clearance of inulin as gold standard. Methods and Findings The study included 10,610 participants referred to the Renal and Metabolic Function Exploration Unit of Edouard Herriot Hospital (Lyon, France). GFR was measured by urinary inulin clearance (only first measurement kept for analysis) then estimated with isotope dilution mass spectrometry (IDMS)–traceable CKD-EPI and Schwartz equations. The participants’ ages ranged from 3 to 90 y, and the measured GFRs from 3 to 160 ml/min/1.73 m2. A linear mixed-effects model was used to model the bias (mean ratio of estimated GFR to measured GFR). Equation reliability was also assessed using precision (interquartile range [IQR] of the ratio) and accuracy (percentage of estimated GFRs within the 10% [P10] and 30% [P30] limits above and below the measured GFR). In the whole sample, the mean ratio with the CKD-EPI equation was significantly higher than that with the Schwartz equation (1.17 [95% CI 1.16; 1.18] versus 1.08 [95% CI 1.07; 1.09], p < 0.001, t-test). At GFR values of 60–89 ml/min/1.73 m2, the mean ratios with the Schwartz equation were closer to 1 than the mean ratios with the CKD-EPI equation whatever the age class (1.02 [95% CI 1.01; 1.03] versus 1.15 [95% CI 1.13; 1.16], p < 0.001, t-test). In young adults (18–40 y), the Schwartz equation had a better precision and was also more accurate than the CKD-EPI equation at GFR values under 60 ml/min/1.73 m2 (IQR: 0.32 [95% CI 0.28; 0.33] versus 0.40 [95% CI 0.36; 0.44]; P30: 81.4 [95% CI 78.1; 84.7] versus 63.8 [95% CI 59.7; 68.0]) and also at GFR values of 60–89 ml/min/1.73 m2. In all patients aged ≥65 y, the CKD-EPI equation performed better than the Schwartz equation (IQR: 0.33 [95% CI 0.31; 0.34] versus 0.40 [95% CI 0.38; 0.41]; P30: 77.6 [95% CI 75.7; 79.5] versus 67.5 [95% CI 65.4; 69.7], respectively). In children and adolescents (2–17 y), the Schwartz equation was superior to the CKD-EPI equation (IQR: 0.23 [95% CI 0.21; 0.24] versus 0.33 [95% CI 0.31; 0.34]; P30: 88.6 [95% CI 86.7; 90.4] versus 29.4 [95% CI 26.8; 32.0]). This study is limited by its retrospective design, single-center setting with few non-white patients, and small number of patients with severe chronic kidney disease. Conclusions The results from this study suggest that the Schwartz equation may be more reliable than the CKD-EPI equation for estimating GFR in children and adolescents and in adults with mild to moderate kidney impairment up to age 40 y., In this retrospective cross-sectional study, Luciano da Silva Selistre and colleagues compare Schwartz and CDK-EPI equations for estimating glomerular filtration rate in patients of different ages and degrees of renal impairment., Editors' Summary Background Throughout life, our kidneys filter waste products (from food and from the normal breakdown of tissues) and excess water from our blood to make urine. If our kidneys stop working for any reason, the rate at which they filter the blood (the glomerular filtration rate, or GFR) decreases, and dangerous amounts of creatinine and other waste products build up in the blood. Kidneys can stop working suddenly, but in chronic kidney disease (CKD), a condition that affects more than 10% of the world’s population, kidney function declines gradually over many years. The symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, especially at night. CKD cannot be cured, but its progression can be slowed by controlling high blood pressure and diabetes and by adopting a healthy lifestyle; the same interventions also reduce the chance of CKD developing in the first place. Why Was This Study Done? CKD is linked with an increased risk of end-stage renal (kidney) disease and cardiovascular disease. Early identification of CKD can prevent these life-threatening complications, so clinical practice guidelines have been proposed for the diagnosis and management of CKD in the general population. The assessment of GFR is central to these guidelines. GFR can be measured by infusing inulin, a compound that is eliminated from the body by glomerular filtration, into the blood and measuring its rate of appearance in the urine. However, in routine clinical practice, GFR is usually estimated from blood creatinine levels using a GFR estimating equation (creatinine levels vary considerably within and between individuals, so an equation is needed to convert measured creatinine levels into GFR estimates). Examples of creatinine-based GFR estimation equations include the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Schwartz equation, which were developed in middle-aged adults and children, respectively. Few studies have evaluated the performance of such equations over all ages and levels of kidney impairment, so here the researchers assess the reliability of the CKD-EPI and Schwartz equations for estimating GFR in children, adolescents, and adults. What Did the Researchers Do and Find? In 10,610 individuals referred to a single French hospital because of suspected or established kidney disease or before kidney donation, the researchers compared GFR measured by inulin clearance with GFR estimated using the CKD-EPI and Schwartz equations. They evaluated the reliability of each equation by calculating the average (mean) ratio of estimated GFR to measured GFR (a ratio of 1 indicates that the equation yielded GFR values identical to those from the gold-standard inulin clearance test) and by assessing the precision and accuracy of the estimated GFR values: the precision of a measurement indicates its reproducibility and reliability; the accuracy of a measurement indicates its closeness to the true value of a quantity. Across all the participants, the mean ratio of estimated GFR to measured GFR with the Schwartz equation was nearer to 1 than the mean ratio for the CKD-EPI equation. Among participants of all ages with measured GFR values indicating mild loss of kidney function, the mean ratio obtained with Schwartz equation was also nearer to 1 than that obtained with the CKD-EPI equation. Among young adults (18–40 years old) with measured GFR values indicating mild to moderate loss of kidney function, the Schwartz equation had better precision and was more accurate than the CKD-EPI equation, but, in all patients aged ≥65 years, the CKD-EPI equation performed better than the Schwartz equation. Finally, in children and adolescents, the Schwartz equation performed better than the CKD-EPI equation. What Do These Findings Mean? Several aspects of this study (for example, its single-site setting and the low numbers of participants with severe CKD) may limit the accuracy and generalizability of its findings. However, these findings suggest that the Schwartz equation may be more reliable than the CKD-EPI equation for estimating GFR in children and adolescents and in adults up to 40 years old with mild to moderate kidney impairment. Up to now, there has been no consensus about when physicians should switch from using the Schwartz equation (which was developed in children) to using the CKD-EPI equation (which was developed in middle-aged adults) to estimate GFR in their patients. The findings of this study might therefore help physicians decide when to make this switch, thereby improving clinical decision-making and possibly helping to reduce the global burden of CKD. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001979. The UK National Health Service Choices website provides information for patients on chronic kidney disease, including information on screening for and diagnosing CKD and some personal stories about the disease The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease and about the estimation of glomerular filtration rates (in English and Spanish) The US National Institute of Diabetes and Digestive and Kidney Diseases provides links to information about all aspects of kidney disease and information on creatinine-based GFR estimation equations; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish) World Kidney Day, a joint initiative of the International Society of Nephrology and the International Federation of Kidney Foundations, aims to raise awareness about kidneys and kidney disease Clinical guidelines for the evaluation and management of CKD produced by the Kidney Disease Improving Global Outcomes not-for-profit foundation are available MedlinePlus provides links to additional resources about kidney diseases

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 (AGT). 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 (GFR) decreases due to progressive renal involvement, oxalate accumulates and results in systemic oxalosis. Diagnosis is still often delayed. It may be established on the basis of clinical and sonographic findings, urinary oxalate +/- glycolate assessment, DNA analysis and, sometimes, direct AGT activity measurement in liver biopsy tissue. The initiation of conservative measures, based on hydration, citrate and/or phosphate, and pyridoxine, in responsive cases at an early stage to minimize oxalate crystal formation will help to maintain renal function in compliant subjects. Patients with established urolithiasis may benefit from extracorporeal shock-wave lithotripsy and/or JJ stent insertion. Correction of the enzyme defect by liver transplantation should be planned, before systemic oxalosis develops, to optimize outcomes and may be either sequential (biochemical benefit) or simultaneous (immunological benefit) liver-kidney transplantation, depending on facilities and access to cadaveric or living donors. Aggressive dialysis therapies are required to avoid progressive oxalate deposition in established end-stage renal disease (ESRD), and minimization of the time on dialysis will improve both the patient's quality of life and survival.

Background. Children with primary hyperoxaluria type 1 (PH 1) often develop severe growth failure, which is related to metabolic and endocrine consequences of chronic renal failure, and/or oxalate deposition in bone and cartilage. Combined liver and kidney transplantation (LKT) corrects the underlying metabolic defect and restores renal function in these children. Methods. We therefore analyzed longitudinal growth of 24 children with PHI who underwent LKT at nine European centers. Mean age at LKT was 8.9 years, and mean duration of follow-up was 5.7 years. Results. After LKT mean standardized height tended to increase from -1.79 SD to -1.47 SD until last observation. Mean adult height amounted to 167 cm and 158 cm in boys and girls, respectively. At last observation, seven out of 24 patients were stunted. Within the whole study population, the degree of catch-up growth after LKT was positively associated with degree of stunting at the time of LKT and negatively associated with prednisolone dosage explaining together 39% of the overall variability. Conclusions. Combined LKT does not induce true catch-up growth in the majority of children with PHI. Due to the preexisting growth retardation at the time of LKT, one third of patients end up with a reduced final height.

Impairment of longitudinal growth in children with chronic renal failure (CRF) is multifactorial. It is mainly due to disturbances in the growth hormone (GH)/insulin-like growth factor (IGF)/IGF-binding protein axis. Growth failure can be managed by optimizing nutrition and fluid/electrolyte homeostasis, and overcoming the growth-inhibiting effects of uremia by high-dose recombinant human (rh) GH treatment. A sufficient catch-up growth is one of the determining issues for the overall success of pediatric kidney transplantation (Tx). However, despite satisfactory renal function, spontaneous catch-up growth is often insufficient as glucocorticoid treatment is the main inhibiting factor for longitudinal growth after Tx. In addition, longitudinal growth may be jeopardized by low glomerular filtration rate (GFR) and African American or Hispanic background. Supraphysiological doses of GH and/or IGF-I in vitro and in vivo can partially overcome the growth-inhibiting effects of glucocorticoid treatment. GH-associated increase of leukocyte proliferation and cytotoxicity with stimulated interferon synthesis have been demonstrated. However, it is not clear whether such stimulatory effects on leukocyte function are a transitory or a constant risk factor after organ Tx. Clinical trials of GH in children after renal Tx have suggested a rather moderate or transient effect of rhGH on the immune system, and corticosteroids induce a hyporesponsiveness to the action of GH. As long as corticosteroids are believed to be essential after renal Tx, rhGH should be considered to optimize longitudinal growth in children.

Recent advances in the knowledge of physiology, genetics, imaging, and therapeutics have lead to novel practical approaches in paediatric nephrology. Many inherited syndromes have been revisited in order to identify precise renal diseases at the molecular level. In addition, a large number of epidemiological studies and clinical trials have allowed guidelines and recommendations to be provided for chronic and end-stage renal failure, urinary tract infection, glomerular diseases, etc.

Recurrence of nephrotic syndrome after renal transplantation leads to graft loss within 1 year in 50-80% of patients who do not receive any specific treatment. Several treatment protocols have been proposed leading to long-term remission in 50-80% of patients. The aim of our study was to evaluate the efficiency of intensified immunosuppression, simultaneously including methylprednisolone pulses, cyclophosphamide, high-dose cyclosporine and plasma exchanges. Fourteen patients with early recurrence were treated with a protracted high-dose prednisone or IV methylprednisolone, oral cyclophosphamide, high-dose oral or IV cyclosporine, and plasma exchanges. By the end of cyclophosphamide therapy and plasma-exchange program, six out of 14 patients had no proteinuria; five had residual proteinuria without nephrotic syndrome and three experienced ongoing gross proteinuria with nephrotic syndrome. By the end of follow-up, four out of the 14 patients had lost their graft: one out of six with complete remission, one out of five with residual proteinuria and two out of three with persistent nephrotic syndrome. We conclude that multiple reinforcement of immunosuppression in patients with recurrent nephrotic syndrome following renal transplantation as performed in our patients is not more efficient than the single use of cyclophosphamide or plasma exchange or high-dose cyclosporine as reported in the literature.

Objective To describe the clinical and laboratory manifestations of childhood-onset systemic lupus erythematosus (SLE) at presentation. Study design This retrospective French multicenter study involved 155 patients in whom SLE developed before the age of 16 years. Mean patient age at onset was 11.5 ± 2.5 years (range, 1.5-16 years). The female to male ratio was 4.5. Results The most common initial manifestations were hematologic (72%), cutaneous (70%), musculoskeletal (64%), renal (50%), and fever (58%). Thirty-two percent of children had atypical symptoms, mainly including abdominal involvement in 26 patients, which lead to negative laparotomy results for presumed appendicitis. Severe renal, neurologic, hematologic, abdominal, cardiac, pulmonary, thrombotic, and/or cutaneous manifestations occurred within the first month after the diagnosis in 40% of patients. The mean erythrocyte sedimentation rate was 72 ± 29 mm/h, and the mean C-reactive protein value 22 ± 21 mg/L. Antinuclear antibodies an, anti-double stranded DNA antibodies, and low C3 or C4 level were retrieved in 97%, 93%, and 78 % of patients, respectively. Conclusion Initial manifestations of childhood-onset SLE are diverse and often severe. The diagnosis of SLE should be promptly considered in any febrile adolescent with unexplained organ involvement, especially when associated with an increased erythrocyte sedimentation rate.

Nephrotoxicity is a well-known adverse effect of cyclosporine A (CyA) treatment in children with steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome (NS). We analyzed nine children (age: 3.3-15.7 years, two girls) with SD or SR NS who experienced a significant decrease in their GFR under CyA treatment as measured by inulin clearance (C(IN)). Mycophenolate mofetil (MMF) was introduced progressively until doses of 1 g/1.73 m(2) twice daily were reached. CyA treatment was stopped after introduction of MMF and oral steroids were reduced if possible. After a median follow up of 261 days, no adverse effects of MMF such as diarrhea or hematological anomalies occurred in our patients. After switching from CyA to MMF, those children with SD NS remained in remission without proteinuria and those with SR NS did not show any significant changes in their residual proteinuria. The serum protein level did not change significantly in any of the children analyzed. GFR increased from a mean of 76.9+/-4.8 to 119.9+/-5.9 mL/1.73 m(2) per min (P0.001). Oral steroid treatment could be reduced from a median [range] prednisone dose of 0.85 [0.26-2.94] mg/kg/d pre-MMF to 0.29 [0-1.1] mg/kg per day (P=0.026), and blood pressure decreased moderately after CyA withdrawal, but the difference did not reach statistical significance. We conclude that a switch from CyA to MMF seems to be safe for children with SDNS and SRNS in terms of side effects as well as disease control, at least in the short term. Interruption of CyA treatment lead to rapid amelioration of kidney function in these children, often associated with steroid sparing, which may lead to additional benefit for growth velocity, blood pressure and physical appearance.

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism, in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of disease, ranging from renal failure in infancy to mere renal stones in late adulthood. This disease is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT), which is encoded by a single copy gene, AGXT, located in 2q37.3. We identified an apparently homozygous, loss-of-function, mutation in a patient; the gene defect was present in the heterozygous mother but not in the patient's father. We performed a microsatellite repeat analysis using 13 specific chromosome 2 markers and non-chromosome 2 minisatellites. Six specific chromosome 2 markers showed an apparently homozygous maternal inheritance while four showed a biparental transmission consistent with paternity (confirmed by minisatellite analysis). Quantitative PCR of AGXT exons 1 and 3 on the patient's and parents genomic DNA revealed the presence of two copies of the gene. This is the first case of PH1 caused by segmental maternal isodisomy of 2q37.3.

Resume Objectifs. – L'objectif de cette etude a ete d'analyser retrospectivement la survie et les facteurs de mortalite dans la population des enfants ayant beneficie d'une transplantation renale a l'hopital Edouard-Herriot a Lyon. Patients et methodes. – Entre avril 1987 et janvier 2002, 194 enfants ont ete transplantes. Nous avons recueilli les donnees concernant l'âge au moment de la transplantation, la methode d'epuration extrarenale avant la transplantation, le type de donneur (vivant apparente : DVA ou en etat de mort encephalique : DME) ainsi que l'evolution pour tous les patients. Onze enfants sont decedes durant cette periode pour lesquels les facteurs de morbidite et de mortalite ont ete etudies. Resultats. – L'âge moyen au moment de la greffe etait de 9,5 ans (extremes : 0,6–17,9 ans) et 16 enfants ont ete transplantes avant l'âge de deux ans. Il s'agissait d'une premiere transplantation dans 86 % des cas, d'une seconde dans 10 % des cas et d'une troisieme dans 3 % des cas. Un tiers des enfants a ete transplante de facon preemptive. La greffe a ete realisee a partir d'un DVA dans 18 % des cas et a partir d'un DME dans 82 % des cas. Parmi les 11 enfants decedes (5,7 %), quatre avaient ete transplantes a deux reprises. Les deces sont survenus en moyenne 2,4 ans (extremes : 2 jours–6,3 mois) apres la transplantation. Cinq d'entre eux ont presente un rejet aigu traite par perfusion de methylprednisolone et orthoclone OKT 3, quatre ont eu une infection a cytomegalovirus (CMV) et trois ont necessite une reintervention chirurgicale. Les deces ont ete imputes a des infections bacteriennes (4/11), a une infection a CMV (2/11), a des complications neurologiques (2/11), a un lymphome de Burkitt (1/11) et dans deux cas la mort est restee inexpliquee (2/11). Conclusion. – Les infections bacteriennes restent la premiere cause de mortalite en transplantation renale chez l'enfant. L'amelioration de la survie globale passe probablement par une plus grande vigilance vis-a-vis des infections nosocomiales et par une limitation de l'immunosuppression initiale.

Background. Organ transplant recipients taking immunosuppressants are at increased risk of skin cancer. Although several studies have been devoted to adult transplant patients, few data are available on the long-term skin malignancies following pediatric organ transplantation. Objective. The objective of this study was to present the current state of knowledge on skin malignancies in patients who received their graft during childhood. Methods. This study reviews data from the literature and includes our personal experience. Results. Skin cancer is the most frequent malignancy following pediatric renal transplantation and the second most common after pediatric nonrenal transplantation. Skin cancers mainly include squamous and basal cell carcinomas. The occurrence of skin cancer in transplanted children is an extremely rare event during childhood. By contrast, skin carcinomas develop in early adulthood at an average age of 27 years. Other reported skin malignancies include anogenital carcinomas and melanoma. Cutaneous forms of Kaposi's sarcoma are exceptional in children. Conclusion. The increased risk of skin cancer following pediatric transplantation justifies prevention and adequate education of children and their parents concerning sun avoidance and protection.

Nephrologie & Therapeutique - In Press.Proof corrected by the author Available online since dimanche 25 septembre 2016

Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.

A cross-sectional study was performed to assess quality of life (QoL) after kidney or liver transplantation during childhood. Self-questionnaires explored children, adolescent and parent QoL. Seventy-five transplant children, 36 transplant adolescents, 67 mothers, 34 fathers and 67 caregivers filled out the questionnaires; they were compared with a reference population. Children reported a rather good QoL, but their extra-family involvement appeared not as satisfactory as that of the reference population children. Adolescents reported a very high QoL when completing the structured format scale; however, their responses to open-ended questions showed qualitative differences compared with those of a reference population: they expressed concern about their body or health, less pleasure than ordinary adolescents to manage by themselves, and a poor relationship with peers. Mothers indicated a deep impact of the child's illness on their own QoL, and the need for psychological support. In conclusion, a rather good QoL is a long-lasting feature of kidney and liver transplantation in children. Such an assessment is mandatory to identify remaining impairments in some selected areas, either in the recipient or family.

RTx remains challenging in children under 3 years of age. This single-center study reviewed the medical records of children

Unilateral multicystic dysplastic kidney is one of the most frequently identified urinary tract abnormalities in children. Although it can be an isolated finding, it is often associated with other anomalies of the kidney and urinary tract. It has also been described in association with other multisystemic disorders of known genetic aetiologies. Cowden disease (CD) is a rare autosomal-dominant disorder with age-related penetrance characterized by benign and malignant hamartomatous lesions affecting derivatives of all three germ cell layers. Hamartomas can emerge in virtually every organ, but are mostly found in the skin and gastrointestinal tract. We report a 7-year-old patient presenting with unilateral multicystic dysplastic kidney and CD, a hitherto unknown association in paediatrics, which raises the question of an increased risk of renal cancer.

Summary 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.

BACKGROUND AND OBJECTIVES: Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. RESULTS: Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3-72.1) years and median diagnosis delay was 1.3 (0-45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8-70.7). Among the 314 patients aged ≥16 years, using the last available plasma creatinine, 22.5% had an eGFR≥90 ml/min per 1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15-29, and

Background. The pharmacokinetics and immunodynamics of basiliximab were assessed in 39 pediatric de novo kidney allograft recipients to rationally chose a dose regimen for this age group. Methods. In study part 1, patients were given 12 mg/m 2 of basiliximab by bolus intravenous injection before surgery and on day 4. An interim pharmacokinetic evaluation supported a fixed-dose approach for study part 2 in which infants and children received two 10-mg doses and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for analysis of basiliximab and soluble interleukin-2 receptor concentrations, flow cytometry, and screening for anti-idiotype antibodies. Results. Basiliximab clearance in infants and children (n=25) was reduced by approximately half compared with adults from a previous study and was independent of age (1-11 years), weight (9-37 kg), and body surface area (0.44-1.20 m 2 ). Clearance in adolescents (12-16 years, n=14) approached or reached adult values. CD25-saturating basiliximab concentrations were maintained for 31±12 days in study part 1 with mg/m 2 dosing and for 36±14 days in study part 2 based on the fixed-dose regimen (P=0.31). A single patient experienced a rejection episode during CD25 saturation. The duration of CD25 saturation in patients who experienced a rejection episode after desaturation did not differ from those who remained rejection-free for the full 6-month period: 34±6 days (n=6) vs. 35±14 days (n=33 patients); P=0.74. Anti-idiotype antibodies were detected in two patients; however, this did not influence the clearance of basiliximab or the duration of CD25 saturation. Conclusions. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients

Resume Le risque infectieux est plus important chez l’enfant transplante que chez l’adulte car les enfants sont moins souvent immunises contre les agents infectieux et sont plus exposes que les adultes a de nombreux agents infectieux (virus mais egalement bacteries dont le pneumocoque). L’application du calendrier vaccinal standard doit etre une preoccupation constante des equipes de transplantation (Tx). Certains vaccins non recommandes par le calendrier vaccinal « standard » sont particulierement conseilles pour l’enfant et son entourage familial ainsi que pour les soignants. La reponse vaccinale doit etre evaluee par le suivi serologique avant Tx, en particulier lors du bilan pre-Tx puis periodiquement apres Tx. La seronegativite plus frequente que chez l’adulte pour l’Epstein Barr Virus (EBV) explique une frequence accrue de lymphoproliferations post-Tx a l’âge pediatrique.

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.

Corticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828-836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term.Data regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model.Corticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (-0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected.Early CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children.

Deposition of calcium oxalate crystals in the kidney and bone is a hallmark of primary hyperoxaluria (PH). Since the bone compartment can store massive amounts of oxalate, patients present with recurrent low-trauma fractures, bone deformations, severe bone pains, and specific oxalate osteopathy on X-ray. Bone biopsy from the iliac crest displays specific features such as oxalate crystals surrounded by a granulomatous reaction corresponding to an invasion of bone surface by macrophages. The objective of this manuscript is therefore to provide an overview of bone impairment in PH, by reviewing the current literature on bone and dental symptoms as well as imaging techniques used for assessing bone disease.

Mixed Connective Tissue Disease (MCTD) is a rare autoimmune disease of unknown origin. The diagnosis is suggested when there are overlaping symptoms of lupus, scleroderma and dermatomyositis. Kasukawa criteria are the most commonly used in pediatrics. Treatment should be tailored to the clinical symptoms but no specific recommendation regarding the therapeutic management has been established to date. Tocilizumab (TCZ), an inhibitor of interleukin 6 is used in juvenile idiopathic arthritis (systemic and polyarticular JIA) and Castleman's disease. Only one case has been reported with TCZ in the context of a MCTD with pulmonary hypertension in a 45 year-old man with a favorable outcome.

Contains fulltext : 136370.pdf (Publisher’s version ) (Closed access) Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.

Neonatal atypical hemolytic uremic syndrome (aHUS) is a rare but severe disease that is mainly due to methylmalonic aciduria or genetic complement abnormalities. Traditional management of aHUS includes plasma infusion/exchange, but in small or unstable infants, plasma exchange can be challenging because of high extracorporeal volume and difficulty to obtain an adequate venous access. The C5 complement blocker eculizumab has become a cornerstone of first-line management of aHUS due to complement deregulation in older patients. However, little data are available on its use in neonatal aHUS. We report on an 11-day-old neonate with severe aHUS (myocardial impairment, respiratory failure, acute kidney disease requiring hemodiafiltration) due to homozygous factor-H deficiency. She received early treatment with eculizumab as first-line therapy and completely recovered within 5 days. A second dose of eculizumab was administered 7 days after the first infusion, followed by a dose every 2 weeks for 2 months and then every 3 weeks, at the same dosage (300 mg). With more than 24 months of follow-up, renal function remains normal. We report on the long-term efficacy and safety of eculizumab as first-line therapy in neonatal aHUS. However its use still requires optimization in terms of indications and administration (frequency, dosage).

International audience; Developing guidelines on a subject as broad as hypertension is difficult, especially when the guidance relates to hypertension in the chronic kidney disease (CKD) population. The Kidney Disease: Improving Global Outcomes Guideline Development Group has applied a rigorous methodology in reviewing all available evidence, and their recommendations are consistent with the evidence-based approach. As a result, the European Renal Best Practice endorses most of its recommendations. However, the Work Group feels that some additional advice could help clinicians in daily practice: (i) individualization of treatment should be taken into account, especially (cardiovascular) co-morbidities, age, gender and race; (ii) side-effects, such as postural dizziness should be monitored closely, particularly in elderly, diabetics and patients with arterial stiffness; (iii) the importance of salt restriction should not be neglected; (iv) although angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blocker (ARBs) remain a cornerstone in the management of hypertension, and especially cardiovascular protection, in some particular situations such as in advanced CKD and in patients without proteinuria, their role is less well defined; (v) as most CKD patients need more than one antihypertensive drug to achieve blood pressure control, the specific (renal) (dis)advantages of other classes than ACE-I or ARB should be taken into account.

The purpose of this Clinical Practice Guideline is to provide guidance on evaluation of the kidney donor and transplant recipient as well as on the management of the recipient in the perioperative period. It is designed to provide information and aid decision-making. It is not intended to de#64257;ne a standard of care, and should neither be construed as one nor should it be interpreted as prescribing an exclusive course of management. The original version of this guideline was published in Nephrology, Dialysis and Transplantation and this current version is a reduced article aiming to disseminate the guideline into Spanish-speaking countries and transplant communities.

Cystinosis is an autosomal recessive disorder, char- acterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-90024del27, which has only been detected in families from this region. Reverse transcription-PCR amplifi- cation of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are pre- dicted to either severely truncate cystinosin or alter its topol- ogy, thus accounting for the severe phenotype of these indi- viduals. The mutation 898-90024del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cysti- nosis in Brittany. 1

The nephrotoxic effects of the antineoplastic drug ifosfamide have been attributed to its hepatic metabolite chloroacetaldehyde. The effects of chloroacetaldehyde on isolated human kidney cortex tubules metabolizing lactate (a physiologic substrate in human kidneys) were investigated. At concentrations of > or =0.5 mM, chloroacetaldehyde was toxic to the human kidney tubules, as demonstrated by a dramatic decrease in cellular ATP levels and a large increase in lactate dehydrogenase release; chloroacetaldehyde also stimulated pyruvate accumulation and inhibited lactate removal and glucose synthesis. These effects, which were associated with incomplete disappearance of chloroacetaldehyde and extensive depletion of the cellular CoA, acetyl-CoA, and glutathione contents, were prevented by the addition of thiol-protecting drugs (mesna and amifostine). Human kidney tubules were demonstrated to metabolize chloroacetaldehyde at high rates, presumably via aldehyde dehydrogenase, which is very active in human kidneys. Carbon-13 nuclear magnetic resonance spectroscopy measurements indicated that human kidney tubules converted [2-(13)C]chloroacetaldehyde to [2-(13)C]chloroacetate, the further metabolism of which was very limited. At equimolar concentrations, chloroacetate was much less toxic than chloroacetaldehyde, indicating that chloroacetate synthesis from chloroacetaldehyde by human kidney tubules represents a detoxification mechanism that could play a role in vivo in preventing or limiting the nephrotoxic effects observed during ifosfamide therapy.

This study examines changes in body composition after renal transplantation (Tx) in 16 children who underwent dual-energy X-ray absorptiometry examination within 6 months preceding Tx; the examination was then repeated every 6 to 12 months after Tx. Body composition was analyzed with regard to whole-body bone mineral content (BMC), lean body mass (LBM), and fat body mass (FBM). Median BMC decreased from the initial value of +0.98 standard deviation scores (SDS) to [minus ]0.55 SDS during the first 3 months after Tx, and a further decrease was noted at the end of month 6 (M6; [minus ]1.34 SDS) and M12 after Tx ([minus ]1.32 SDS). Improvement was observed during the second year after Tx ( P for global changes [lt ] 0.0001). LBM and FBM also changed significantly during the 2 years after Tx ( P [equals] 0.006 and P [equals] 0.0001, respectively). LBM decreased during the first 3 months after Tx (median change, 0.71 SDS) and remained less than 0 SDS in all but 4 patients. Median LBM did not decrease to less than [minus ]1 SDS during the entire study period. Conversely, median FBM increased by a median of 3.73 SDS during the first 3 months and remained elevated during the first 12 months after Tx, with a subsequent decrease at 2 years after Tx. No significant correlation was found between cumulative doses of prednisone and BMC, FBM, or LBM at any interval if absolute values were considered. However, relative changes in FBM correlated significantly with relative changes in prednisone cumulative doses. [copy ] 2001 by the National Kidney Foundation, Inc.

Background. The prevalence and significance of vesicoureteral reflux (VUR) after kidney transplantation in adults varies between authors and there have been few reports in children. Methods. We conducted a retrospective study in a single-centre paediatric cohort. Fifty-five of the 84 children who underwent kidney transplantation over a 5-year period were checked with routine cystography after a median of 8 months post-transplantation. Graft function and urinary-tract infections were assessed during the first 6 years after transplantation. Results. VUR into the graft was present in 58% of the patients. Graft function and incidence of urinary-tract infections were similar in the two groups, independent of VUR. After having excluded infections attributed to the presence of a catheter, actuarial survival rates without pyelonephritis and without pyelonephritis following a first lower urinary-tract infection were worse in patients with VUR (P=0.017 and P=0.0039 respectively). None of the eight patients with VUR treated with antibiotic prophylaxis after a first acute pyelonephritis (APN) episode presented subsequent APN after 4.4 ± 3.3 years on therapy. Conclusions. VUR to the graft occurred in more than half paediatric renal transplant recipients. This condition was associated with an increased risk of APN. Long-term antibiotic prophylaxis seems to be able to prevent APN in transplanted children with VUR.

Background The use of cyclosporin (CsA) has improved graft survival in transplant (Tx) patients despite its potential nephrotoxicity. Children born to transplanted women may present with intrauterine growth retardation (IUGR). On the basis of potential reduced nephron mass both in IUGR and in newborn experimental animals exposed to CsA in utero, we investigated the renal function of children >1 year of age born to women under maintenance immunosuppression, including CsA. Methods Fourteen children born to 12 Tx women (nine kidney, one pancreas-kidney, one heart, one liver) were investigated using inulin clearance (C(in)), para-aminohippuric acid clearance (C(PAH)), microalbuminuria, and electrolyte reabsorption rate. Results Gestational age of the 14 infants was 34+/-3 weeks and birth weight 2018+/-620 g. During pregnancy, CsA trough blood level was 234+/-115 microg/l and plasma creatinine range was 96-136 micromol/l. Two children were excluded from the study because renal investigation led to a diagnosis of hereditary nephritis (one Alport syndrome, one familial dominant focal segmental glomerulosclerosis) that was retrospectively completed in the mother. Renal function tests were finally performed in 12 children at 2.6+/-1.8 years of age: BP 94+/-7/55+/-5 mmHg, C(in) 117+/-28 ml/min/1.73 m(2), C(PAH) 545+/-124 ml/min/1.73 m(2), filtration fraction 0.23+/-0.03, microalbuminuria 4.2+/-3.5 mg/mmol. Electrolyte tubular reabsorption rates and urine concentrating capacity were normal. Conclusion These results suggest that in children born to transplanted women taking CsA, renal function develops normally despite prolonged exposure in utero.

Primary hyperoxalurias (PH) are very rare diseases characterised by overproduction and accumulation of oxalate in the body. The main target organ is the kidney, as oxalate cannot be metabolised and is excreted in the urine, leading to nephrocalcinosis, recurrent urolithiasis, and subsequent renal impairment. During the last decade, major advances in enzymology, molecular genetics, and cell biology have generated excellent reviews on both pathophysiology and management1 2; however, specific questions remain unanswered. Basically, hyperoxaluria (normal urinary oxalate

We report two cases of children who presented with haemolytic uraemic syndrome following varicella infection. One of them had a membrane cofactor protein mutation, and the other had anti-factor H antibodies. These observations show that infectious agents such as varicella-zoster virus may be the trigger of haemolytic uraemic syndrome in patients with complement dysregulation.

Bedwetting is a common world-wide finding in school-age children (around 7% of 7-year-old children); it can be related to monosymptomatic nocturnal enuresis (MNE) in more than half of cases and to bladder dysfunction in the remainder. In most subjects, the diagnostic procedure is limited to patient and family history since physical examination is normal. The pathophysiology of MNE remains uncertain. It is likely that there are several kinds of MNE according to clinical features (polyuria? sleep disorders? response to desmopressin? psychopathological problems? primary/secondary trouble?) therefore leading to different therapeutic approaches. From a practical point of view, most patients respond well to either alarm system or desmopressin, which give significant results compared to placebo; tricyclic agents should be avoided because of their potential life-threatening adverse events. Further advances are expected in the pathophysiology and management of such a common disorder.