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10 p.-4 fig.-2 tab. 1 graph. abst., Background: C3 glomerulopathy is a rare and heterogeneous complement-driven disease. It is often challenging to accurately predict in clinical practice the individual kidney prognosis at baseline. We herein sought to develop and validate a prognostic nomogram to predict long-term kidney survival., Methods: We conducted a retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. The dataset was randomly divided into a training group (n = 87) and a validation group (n = 28). The least absolute shrinkage and selection operator (LASSO) regression was used to screen the main predictors of kidney outcome and to build the nomogram. The accuracy of the nomogram was assessed by discrimination and risk calibration in the training and validation sets., Results: The study group comprised 115 patients, of whom 46 (40%) reached kidney failure in a median follow-up of 49 months (range 24–112). No significant differences were observed in baseline estimated glomerular filtration rate (eGFR), proteinuria or total chronicity score of kidney biopsies, between patients in the training versus those in the validation set. The selected variables by LASSO were eGFR, proteinuria and total chronicity score. Based on a Cox model, a nomogram was developed for the prediction of kidney survival at 1, 2, 5 and 10 years from diagnosis. The C-index of the nomogram was 0.860 (95% confidence interval 0.834–0.887) and calibration plots showed optimal agreement between predicted and observed outcomes., Conclusions: We constructed and validated a practical nomogram with good discrimination and calibration to predict the risk of kidney failure in C3 glomerulopathy patients at 1, 2, 5 and 10 years., Work on this study was supported by the Instituto de Salud Carlos III / Fondo Europeo de Desarrollo Regional (ISCIII/FEDER; grants PI16/01685 and PI19/1624) and Red de Investigación Renal (RD12/0021/0029; to M.P.) and the Autonomous Region of Madrid (S2017/BMD-3673; to M.P.). S.R.d.C. is supported by the Ministerio de Economia y Competitividad (grant PID2019-104912RB-I00) and the Autonomous Region of Madrid (grant S2017/BMD-3673).

Additional file 1. Additional Tables.

Background: High dose methotrexate (HDMTX) is used for the treatment of pediatric hemato-oncological diseases. HDMTX can induce acute kidney injury in cases of delayed elimination. The use of leucovorin remains the most effective rescue action. Further treatment options are of difficult access in the rare cases where leucovorin fails to prevent renal failure from occurring. Glucarpidase is an effective treatment in cases of methotrexate (MTX) delayed elimination, but cost is high and availability is limited. Charcoal hemoperfusion (CHP) is a very efficient procedure to remove protein-bound drugs, promoting fast MTX elimination, but is rarely considered as a treatment option. Methods: We present three pediatric cases with prolonged exposure to MTX after HDMTX and delayed elimination in which hemoperfusion was performed as rescue treatment for methotrexate intoxication. Results: Charcoal hemoperfusion was performed with positive results and no complications as bridging until glucarpidase was available in two cases and in one case where two doses of glucarpidase led to insufficient reduction of MTX levels. Conclusions: CHP can be considered as a rescue treatment option in MTX intoxication, since it is an effective and safe extracorporeal method for removing MTX, in cases where rescue with leucovorin is insufficient and glucarpidase is not available or while waiting for delivery.

12 p.-4 fig.-4 tab., BACKGROUND AND OBJECTIVES: C3 glomerulopathy is a complement-mediated disease arising from abnormalities in complement genes and/or antibodies against complement components. Previous studies showed that treatment with corticosteroids plus mycophenolate mofetil (MMF) was associated with improved outcomes, although the genetic profile of these patients was not systematically analyzed. This study aims to analyze the main determinants of disease progression and response to this therapeutic regimen., DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective, multicenter, observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy (n=81) or dense deposit disease (n=16) between January 1995 and March 2018 were enrolled. Multivariable and propensity score matching analyses were used to evaluate the association of clinical and genetic factors with response to treatment with corticosteroids and MMF as measured by proportion of patients with disease remission and kidney survival (status free of kidney failure)., RESULTS: The study group comprised 97 patients (84% C3 glomerulopathy, 16% dense deposit disease). Forty-two patients were treated with corticosteroids plus MMF, and this treatment was associated with a higher rate of remission and lower probability of kidney failure (79% and 14%, respectively) compared with patients treated with other immunosuppressives (24% and 59%, respectively), or ecluzimab (33% and 67%, respectively), or conservative management (18% and 65%, respectively). The therapeutic superiority of corticosteroids plus MMF was observed both in patients with complement abnormalities and with autoantibodies. However, patients with pathogenic variants in complement genes only achieved partial remission, whereas complete remissions were common among patients with autoantibody-mediated forms. The main determinant of no remission was baseline proteinuria. Relapses occurred after treatment discontinuation in 33% of the patients who had achieved remission with corticosteroids plus MMF, and a longer treatment length of MMF was associated with a lower risk of relapse., CONCLUSIONS: The beneficial response to corticosteroids plus MMF treatment in C3 glomerulopathy appears independent of the pathogenic drivers analyzed in this study., Work in this study was supported by the Instituto de Salud CarlosIII/ Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to M. Praga), and the Autonomous Region of Madrid (S2017/BMD-3673) (to S. Rodríguez de Córdoba and M. Praga).E. Goicoechea de Jorge is supported by the Spanish “Ministerio de Ciencia, Innovación y Universidades” (RYC-2013-13395 and RTI2018-095955-B-100). S. Rodríguez de Córdoba is supported by Ministerio de Economía y Competitividad/FEDER grant SAF2015-66287R and Autonomous Region of Madrid grant S2017/BMD3673.

WOS: 000461762600003, PubMed ID: 30894599, While children approaching end-stage kidney disease (ESKD) are considered at risk of uremic anorexia and underweight they are also exposed to the global obesity epidemic. We sought to investigate the variation of nutritional status in children undergoing chronic peritoneal dialysis (CPD) around the globe. The distribution and course of body mass index (BMI) standard deviation score over time was examined prospectively in 1001 children and adolescents from 35 countries starting CPD who were followed in the International Pediatric PD Network (IPPN) Registry. The overall prevalence of underweight, and overweight/obesity at start of CPD was 8.9% and 19.7%, respectively. Underweight was most prevalent in South and Southeast Asia (20%), Central Europe (16.7%) and Turkey (15.2%), whereas overweight and obesity were most common in the Middle East (40%) and the US (33%). BMI SDS at PD initiation was associated positively with current eGFR and gastrostomy feeding prior to PD start. Over the course of PD BMI SDS tended to increase on CPD in underweight and normal weight children, whereas it decreased in initially overweight patients. In infancy, mortality risk was amplified by obesity, whereas in older children mortality was markedly increased in association with underweight. Both underweight and overweight are prevalent in pediatric ESKD, with the prevalence varying across the globe. Late dialysis start is associated with underweight, while enteral feeding can lead to obesity. Nutritional abnormalities tend to attenuate with time on dialysis. Mortality risk appears increased with obesity in infants and with underweight in older children., International Society for Peritoneal Dialysis; Baxter Health Care; Fresenius Medical Care, The authors gratefully acknowledge the support by the International Society for Peritoneal Dialysis, Baxter Health Care, and Fresenius Medical Care. We also appreciate the continued dedicated support of the IPPN by the medical and nursing staff in all collaborating centers.

Shroff, Rukshana C/0000-0001-8501-1072; /0000-0001-8501-1072; Caliskan, Salim/0000-0002-3316-8032; Dufek, Stephanie/0000-0002-6323-6673; Verrina, Enrico Eugenio/0000-0002-5178-1949; pasini, andrea/0000-0001-8479-8379; Faria, Maria do Sameiro/0000-0002-8061-9289; Bacchetta, Justine/0000-0002-0578-2529 WOS:000459819600014 PubMed ID: 30374605 BackgroundChildren with congenital nephrotic syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children.MethodsWe conducted a retrospective case note review across members of the European Society for Pediatric Nephrology Dialysis Working Group to evaluate dialysis management, complications of dialysis, and outcomes in children with CNS.ResultsEighty children (50% male) with CNS were identified form 17 centers over a 6-year period. Chronic dialysis was started in 44 (55%) children at a median age of 8 (interquartile range 4-14) months. Of these, 17 (39%) were on dialysis by the age of 6months, 30 (68%) by 1year, and 40 (91%) by 2years. Peritoneal dialysis (PD) was the modality of choice in 93%, but 34% switched to hemodialysis (HD), largely due to catheter malfunction (n=5) or peritonitis (n=4). The peritonitis rate was 0.77 per patient-year. Weight and height SDS remained static after 6months on dialysis. In the overall cohort, at final follow-up, 29 children were transplanted, 18 were still on dialysis (15 PD, 3 HD), 19 were in pre-dialysis chronic kidney disease (CKD), and there were 14 deaths (8 on dialysis). Median time on chronic dialysis until transplantation was 9 (6-18) months, and the median age at transplantation was 22 (14-28) months.ConclusionsInfants with CNS on dialysis have a comparable mortality, peritonitis rate, growth, and time to transplantation as infants with other primary renal diseases reported in international registry data. Department of Health [CDF-2016-09-038] Funding Source: Medline

Background. Mutations in hepatocyte nuclear factor 1B (HNF1B) have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Diabetes and other less frequent anomalies have also been described. Variable penetrance and intrafamilial variability have been demonstrated including severe prenatal phenotypes. Thus, it is important to differentiate this entity from others with similar clinical features and perform confirmatory molecular diagnosis. Methods. This study reports the results of HNF1B screening in a cohort of 60 patients from 58 unrelated families presenting with renal structural anomalies and/or non-immune glucose metabolism alterations, and other minor features suggesting HNF1B mutations. Results. This study identified a pathogenic variant in 23 patients from 21 families. The most frequent finding was bilateral cystic dysplasia or hyperechogenic kidneys (87% of patients). Sixty percent of them also fulfilled the criteria for impaired glucose metabolism, and these were significantly older than those patients with an HNF1B mutation but without diabetes or prediabetes (14.4 versus 3.3 years, P < 0.05). Furthermore, patients with HNF1B mutations had higher frequency of pancreatic structural anomalies and hypomagnesaemia than patients without mutations (P < 0.001 and P = 0.003, respectively). Hyperuricaemia and increased liver enzymes were detected in some patients as well. Conclusions. Renal anomalies found in patients with HNF1B mutations are frequently unspecific and may resemble those found in other renal pathologies (CAKUT, ciliopathies). Active searching for extrarenal minor features, especially pancreatic structural anomalies or hypomagnesaemia, could support the indication for molecular diagnosis to identify HNF1B mutations.

Achieving normal growth is one of the most challenging problems in the management of children with chronic kidney disease (CKD). Treatment with recombinant human growth hormone (GH) promotes longitudinal growth and likely enables children with CKD and short stature to reach normal adult height. Here, members of the European Society for Paediatric Nephrology (ESPN) CKD–Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups present clinical practice recommendations for the use of GH in children with CKD on dialysis and after renal transplantation. These recommendations have been developed with input from an external advisory group of paediatric endocrinologists, paediatric nephrologists and patient representatives. We recommend that children with stage 3–5 CKD or on dialysis should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiation of GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH should be given at dosages of 0.045–0.05 mg/kg per day by daily subcutaneous injections until the patient has reached their final height or until renal transplantation. In addition to providing treatment recommendations, a cost-effectiveness analysis is provided that might help guide decision-making., This Evidence-Based Guideline developed by members of the European Society for Paediatric Nephrology CKD-MBD, Dialysis and Transplantation working groups presents clinical practice recommendations for the use of growth hormone in children with chronic kidney disease on dialysis and after renal transplantation.

Objective To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH). Study design Multicentre prospective clinical study on pediatric patients included in the RenalTube database (www.renaltube.com) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study's protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites. Results Twenty-four patients (17 females, from 1 to 17 years of age) were studied. Serum concentrations (X +/- SD) of phosphate and intact parathyroid hormone were 2.66 +/- 0.60 mg/dl and 58.3 +/- 26.8 pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 +/- 294.45 pg/ml (normal < 60 pg/ml). Abnormally high carotid intima media thickness was found in one patient, who was obese and hypertensive as revealed by ABPM, which disclosed arterial hypertension in two other patients. Z scores for echocardiographic interventricular septum end diastole and left ventricular posterior wall end diastole were +0.77 +/- 0.77 and +0.94 +/- 0.86, respectively. Left ventricular mass index (LVMI) was 44.93 +/- 19.18 g/m(2.7), and four patients, in addition to the obese one, had values greater than 51 g/m(2.7), indicative of left ventricular hypertrophy. There was no correlation between these echocardiographic parameters and serum FGF23 concentrations. Conclusions XLH pediatric patients receiving conventional treatment have echocardiographic measurements of ventricular mass within normal reference values, but above the mean, and 18% have LVMI suggestive of left ventricular hypertrophy without correlation with serum FGF23 concentrations. This might indicate an increased risk of cardiovascular involvement in XLH.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. METHODS: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. RESULTS: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. CONCLUSION: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.

Objective: Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described. Methods: The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing. Results: Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median: 11.3 mg/dL) but normal or abnormally high parathyroid hormone (PTH) levels (median: 52 pg/ mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from eight families. These patients had a median serum calcium level of 7.4 mg/dL and hypoparathyroidism (median: PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium: 10.6 mg/dL; median PTH: 65 pg/mL) with no other alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, plys119lle, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351lle, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.lle816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup). Conclusions: Patients with CASR mutations may not fit the classic clinical pictures of hypercalcemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are important for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorders in 82 patients in the study cohort.

BackgroundThere are three principle forms of vascular access available for the treatment of children with end stage kidney disease (ESKD) by haemodialysis: tunnelled catheters placed in a central vein (central venous lines, CVLs), arteriovenous fistulas (AVF), and arteriovenous grafts (AVG) using prosthetic or biological material. Compared with the adult literature, there are few studies in children to provide evidence based guidelines for optimal vascular access type or its management and outcomes in children with ESKD.MethodsThe European Society for Paediatric Nephrology Dialysis Working Group (ESPN Dialysis WG) have developed recommendations for the choice of access type, pre-operative evaluation, monitoring, and prevention and management of complications of different access types in children with ESKD.ResultsFor adults with ESKD on haemodialysis, the principle of “Fistula First” has been key to changing the attitude to vascular access for haemodialysis. However, data from multiple observational studies and the International Paediatric Haemodialysis Network registry suggest that CVLs are associated with a significantly higher rate of infections and access dysfunction, and need for access replacement. Despite this, AVFs are used in only ∼25% of children on haemodialysis. It is important to provide the right access for the right patient at the right time in their life-course of renal replacement therapy, with an emphasis on venous preservation at all times. While AVFs may not be suitable in the very young or those with an anticipated short dialysis course before transplantation, many paediatric studies have shown that AVFs are superior to CVLs.ConclusionsHere we present clinical practice recommendations for AVFs and CVLs in children with ESKD. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system has been used to develop and GRADE the recommendations. In the absence of high quality evidence, the opinion of experts from the ESPN Dialysis WG is provided, but is clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to local expertise and individual patient needs as appropriate.

Molecular diagnosis is a useful diagnostic tool in primary nephrogenic diabetes insipidus (NDI), an inherited disease characterized by renal inability to concentrate urine. The AVPR2 and AQP2 genes were screened for mutations in a cohort of 25 patients with clinical diagnosis of NDI. Patients presented with dehydration, polyuria-polydipsia, failure to thrive (mean ± SD; Z-height -1.9 ± 2.1 and Z-weight -2.4 ± 1.7), severe hypernatremia (mean ± SD; Na 150 ± 10 mEq/L), increased plasma osmolality (mean ± SD; 311 ± 18 mOsm/Kg), but normal glomerular filtration rate. Genetic diagnosis revealed that 24 male patients were hemizygous for 17 different putative disease-causing mutations in the AVPR2 gene (each one in a different family). Of those, nine had not been previously reported, and eight were recurrent. Moreover, we found those same AVPR2 changes in 12 relatives who were heterozygous carriers. Further, in one female patient, AVPR2 gene study turned out to be negative and she was found to be homozygous for the novel AQP2 p.Ala86Val alteration.Genetic analysis presumably confirmed the diagnosis of nephrogenic diabetes insipidus in every patient of the studied cohort. We emphasize that we detected a high presence (50 %) of heterozygous females with clinical NDI symptoms.• In most cases (90 %), inherited nephrogenic diabetes insipidus (NDI) is an X-linked disease, caused by mutations in the AVPR2 gene. • In rare occasions (10 %), it is caused by mutations in the AQP2 gene. What is new: • In this study, we report 10 novel mutations associated with NDI. • We have detected a high presence (50 %) of heterozygous carriers with clinical NDI symptoms.

PubMedID: 28873971 In patients with chronic kidney disease (CKD), renal synthesis of active Vitamin D [1, 25-dihydroxyVitamin D (1, 25(OH)2D)] declines and is associated with hypocalcaemia, secondary hyperparathyroidism and the spectrum of CKD-mineral and bone disorder (MBD). In advanced CKD, active Vitamin D analogues, including alfacalcidol, calcitriol and paricalcitol, are routinely administered. There are few studies on the use of Vitamin D analogues in children with CKD and on dialysis. It is difficult to define bone-specific outcomes that can guide treatment with active Vitamin D analogues in children with CKD-MBD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs has developed recommendations for the use of active Vitamin D therapy in children with CKD and on dialysis. A second document in parallel with this one covers treatment recommendations for native Vitamin D therapy. The WGs have performed an extensive literature review to include systematic reviews and randomized controlled trials in adults and children with CKD and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system was used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. National Institute for Health Research RS holds a fellowship with the National Institute for Health Research (NIHR). Members of the ESPN CKD-MBD Working Group: Belgium: A. Prytula, Ghent University, Utopaed. France: J. Bachetta., University Children’s Hospital, Lyon. Germany: D. Haffner., Hannover Medical School, Hannover. G. Klaus, University Children’s Hospital, Marburg. Hungary: G. Reusz, Semmelweis University, Budapest. Italy: E. Verrina, G. Gaslini Institute, Genoa. The Netherlands: J. Groothoff, Academic Medical Center, Amsterdam. Spain: M.A. Gamero, Reina Sofía Universitary Hospital, Córdoba. Russia: E. Petrosyan, Russian National Research Medical University, Moscow. Turkey: S. A. Bakkaloglu, Gazi University Hospital, Ankara; I. Dursun, Erciyes University Faculty of Medicine, Kayseri. United Kingdom: R. Shroff, Great Ormond Street Hospital, London. Members of the ESPN Dialysis Working Group: Austria: C. Aufricht, Medical University of Vienna, Vienna. Belgium: J. Vande Walle, University Hospital Ghent, Department of Pediatric Nephrology/Urology, Ghent. Czech Republic: K. Vondrak, University Hospital Motol, Charles University Prague, 2nd Faculty of Medicine, Prague. Finland: T. Holtta, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki. France: B. Ranchin, Centre de Référence des Maladies Rénales Héréditaires, Hospices Civils de Lyon and Université Lyon, Lyon. M. Fischbach, Hautepierre University Hospital, Strasbourg. Germany: Claus Peter Schmitt, University of Heidelberg, Heidelberg. Günter Klaus, University Children’s Hospital, Marburg. Greece: Constantinos J. Stefanidis, A. and P. Kyriakou Childrens Hospital, Athens; N. Printza, Aristotle University of Thessaloniki, Thessaloniki. Italy: Alberto Edefonti, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan; E. Verrina, Giannina Gaslini Children’s Hospital, Dialysis Unit, Genova; E. Vidal, University Hospital of Padova, Padova. Lithuania: A. Jankauskiene, Vilnius