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Introduction Currently available biomarkers and Dual-energy X-ray Absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The 2017 KDIGO guidelines on CKD-MBD propose using DXA if it will affect patient management. We set out to determine the clinical utility of DXA and routine clinical biomarkers by comparing them with tibial cortical BMD measured by peripheral Quantitative Computed Tomography (pQCT), which clearly defines cortical and trabecular compartments and predicts future fracture risk. Methods We performed a prospective multi-centre cross-sectional study in 97 children (5–19 years) with CKD stages 4–5 and on dialysis. Children underwent hip and lumbar spine DXA and tibial pQCT. All DXA and pQCT data were expressed as age corrected Z-scores, and lumbar spine DXA was additionally corrected for height (BMAD Z-score). Imaging findings were correlated with routine serum biomarkers. Results Hip Z-score and lumbar spine BMAD Z-scores correlated significantly with each other (p PTH showed a positive correlation with tibial trabecular BMD (p=0.024) and a negative correlation with cortical BMD (p On multivariable linear regression analysis the significant and independent predictors of tibial cortical BMD were PTH (β-0.355, p Conclusions Routinely used biomarkers- calcium, alkaline phosphatase and PTH- when used together are weak to moderate predictors of BMD. No associations were seen with hip or lumbar spine DXA. DXA is not a clinically useful tool and should not be performed routinely.

Background and Aims In CKD dysregulated calcium (Ca) homeostasis is common and causally associated with reduced bone mineral density (BMD) and vascular calcification. Currently available radiological measures and biomarkers do not allow accurate evaluation of BMD. The aim of our study was to determine the sensitivity and specificity of stable Ca isotopes in determining bone mineral content. Method We measured stable Ca isotopes 44Ca and 42Ca by plasma-ionization mass-spectrometry in blood and urine. The relationship between bone Ca gain and loss is calculated using a compartment model based on Ca kinetics, and expressed as δ44/42Ca. Ca absorption from bones increases δ44/42CaBlood and δ44/42CaUrine, and resorption decreases these fractions. 104 children in CKD4-5 and on dialysis (CKD4-5D), 40 matched controls and 100 adults underwent Ca isotope measurement, bone biomarkers, dual energy x-ray absorptiometry (DXA) and tibial peripheral quantitative CT scan (pQCT), an accurate measure of cortical BMD. Results In healthy children the δ44/42CaBlood and δ44/42CaUrine were higher than in adults (p In CKD2-5D δ44/42CaBlood positively correlated with cholecalciferol (p=0.01) and alfacalcidol (p=0.002) doses, implying increased bone Ca uptake when Ca bioavailability is increased. δ44/42CaBlood positively correlated with biomarkers of bone formation (alkaline phosphatase, p=0.05) and negatively with bone resorption markers (PTH, p=0.013; TRAP5b, p Conclusion Ca isotope ratios provide a novel, non-invasive method of assessing bone mineralization. Further studies are in progress to define optimal levels of δ44/42CaBlood that can guide safe and effective treatment to prevent Ca deficiency or overload.

Background and Aims The determination of dry weight (DW) in children on chronic hemodialysis (HD) remains problematic. No method has been shown superior for DW assessment in the few pediatric studies exploring the utility of inferior vena cava expiratory and inspiratory diameter diameter (IVCDe, IVCDi) and BIS against clinical criteria. We aimed to compare the performance of IVCD, BIS and clinical judgement in DW prediction in hemodialyzed children. Method IVCD and BIS were measured serially pre and post the midweek HD session. IVCDi, IVCDe and IVC contractility index (IVCCI) associations with: (1) BIS estimated (BIS-relOH) and (2) clinically assessed hydration status (OHc) based on deviation from DW were explored. The interpretation of IVC measurements was based on previously published pediatric reference values. The level of agreement between the three tools in fluid overload recognition was studied. Results Fifty-two sets of measurements were undertaken in 13 patients (median age 11 years). OHc and BIS-relOH were positively associated to each other (r=0,5, p Conclusion IVCD measurements alone are not reliable for accurate fluid status prediction in hemodialyzed children as they seem to underestimate fluid overload compared to BIS and clinical criteria. Further studies are warranted to explore the applicability of new technologies for DW assessment of dialysis patients.

Glomerular crescents in kidney transplantation are indicative of severe glomerular injury and constitute a hallmark of RPGN. Their concurrence with ABMR has been rarely described only in adult patients. We report a case of 10-year-old boy with compound heterozygous Fin-major Finnish-type congenital nephrotic syndrome, who had received a deceased-donor kidney transplant 5 years before onset of acute kidney injury and nephrotic range proteinuria without hematuria. Kidney allograft biopsy illustrated 6 glomeruli with global sclerosis and 6 with remarkable circumferential or segmental cellular crescents. Negative glomerular immunofluorescence for immune-complex deposits and the absence of serum ANCA eliminated the presence of immune-mediated and ANCA-positive pauci-immune crescentic glomerulonephritis. Diagnosis of ABMR was based on the high levels of HLA class II DSA and the histological evidence of glomerulitis, peritubular capillaritis, and acute tubular injury with positive linear peritubular capillary C4d staining. The patient despite plasmapheresis and enhanced immunosuppressive treatment progressed to end-stage renal disease. We conclude that glomerular crescents may represent a finding of AMBR and possibly a marker of poor allograft prognosis in pediatric patients.

Glomerular crescents in kidney transplantation are indicative of severe glomerular injury and constitute a hallmark of RPGN. Their concurrence with ABMR has been rarely described only in adult patients. We report a case of 10-year-old boy with compound heterozygous Fin-major Finnish-type congenital nephrotic syndrome, who had received a deceased-donor kidney transplant 5 years before onset of acute kidney injury and nephrotic range proteinuria without hematuria. Kidney allograft biopsy illustrated 6 glomeruli with global sclerosis and 6 with remarkable circumferential or segmental cellular crescents. Negative glomerular immunofluorescence for immune-complex deposits and the absence of serum ANCA eliminated the presence of immune-mediated and ANCA-positive pauci-immune crescentic glomerulonephritis. Diagnosis of ABMR was based on the high levels of HLA class II DSA and the histological evidence of glomerulitis, peritubular capillaritis, and acute tubular injury with positive linear peritubular capillary C4d staining. The patient despite plasmapheresis and enhanced immunosuppressive treatment progressed to end-stage renal disease. We conclude that glomerular crescents may represent a finding of AMBR and possibly a marker of poor allograft prognosis in pediatric patients. © 2020 Wiley Periodicals LLC

In this paper, we address the safety of data-driven control for contact-rich manipulation. We propose to restrict the controller’s action space to keep the system in a set of safe states. In the absence of an analytical model, we show how Gaussian Processes (GP) can be used to approximate safe sets. We disable inputs for which the predicted states are likely to be unsafe using the GP. Furthermore, we show how locally designed feedback controllers can be used to improve the execution precision in the presence of modelling errors. We demonstrate the benefits of our method on a pushing task with a variety of dynamics, by using known and unknown surfaces and different object loads. Our results illustrate that the proposed approach significantly improves the performance and safety of the baseline controller. QC 20210607No duplikate with DiVA:1631253

Data-driven approaches for modelling contact-rich tasks address many of the difficulties that analytical models bear. For real-world scenarios, the hardware capabilities constrain the available measurements and consequently, every step of the problem's formulation. In this work, we propose a formulation that encapsulates knowledge from a baseline controller for the contact-rich task of food-cutting. Based on this formulation, we employ deep networks to model the dynamics within a model predictive controller. We design a training process based on curriculum training with learning rate decay for multi-step predictions, which are essential for receding horizon control. Experimental results demonstrate that even with a simple architecture, our model achieves consistently good predictive performance on known and unknown object classes and exhibits a good understanding of the long term dynamics.

Modelling of contact-rich tasks is challenging and cannot be entirely solved using classical control approaches due to the difficulty of constructing an analytic description of the contact dynamics. Additionally, in a manipulation task like food-cutting, purely learning-based methods such as Reinforcement Learning, require either a vast amount of data that is expensive to collect on a real robot, or a highly realistic simulation environment, which is currently not available. This paper presents a data-driven control approach that employs a recurrent neural network to model the dynamics for a Model Predictive Controller. We build upon earlier work limited to torque-controlled robots and redefine it for velocity controlled ones. We incorporate force/torque sensor measurements, reformulate and further extend the control problem formulation. We evaluate the performance on objects used for training, as well as on unknown objects, by means of the cutting rates achieved and demonstrate that the method can efficiently treat different cases with only one dynamic model. Finally we investigate the behavior of the system during force-critical instances of cutting and illustrate its adaptive behavior in difficult cases. QC 20191021

Pediatric kidney Tx has critically altered the outcome in ESRD pediatric patients. The aims of this study were to determine long-term graft and patient survival in a homogeneous ethnic population. We reviewed the medical charts of pediatric kidney Tx performed between 1990 and 2012 in Greece. Seventy-five kidney Txs were performed from LRD and 62 from DD. The 10- and 20-yr graft survival was higher in LRD Tx compared with DD Tx. Both patient and graft survival at 10 and 20 yr after Tx were similar in LRD Tx from grandparents compared with parents (92.9% vs. 93.4% 20-yr patient survival, 71.4% vs. 78.7% and 57.1% vs. 72.1%, 10- and 20-yr graft survival, respectively). However, there was a decreasing tendency in LRD Tx rates in period 2001-2012 compared with period 1990-2000 (47.1% vs. 62.7%). Risk factors for poor five-yr graft survival were DD Tx, and induction treatment with ALG compared with basiliximab, but their effect attenuated at 10 yr after Tx. In conclusion, Tx from LRD may offer efficient survival outcomes irrespective of donor age, suggesting that even older LRD could be an excellent option for the 1st kidney Tx in children and adolescents.

Primary nonsyndromic vesicoureteral reflux (VUR) and VUR with renal hypoplasia/dysplasia (VUR-RHD) are common congenital anomalies of the kidney and urinary tract (CAKUT). Sequence variations of the ROBO2 gene were investigated in children with nonsyndromic VUR or VUR-RHD.Single-strand conformation polymorphism (SSCP) electrophoresis or multiple restriction fragment SSCP (MRF-SSCP), followed occasionally by direct sequencing, was used to screen 103 patients and 200 controls for nucleotide changes. Gene polymorphisms and transposable elements were investigated using bioinformatics.Two single-nucleotide polymorphisms were detected: IVS1-53 and IVS5-31. The frequency of A allele of IVS1-53GA did not differ significantly between patients and controls. IVS1-53 does not affect mRNA splicing according to in silico analysis. IVS5-31AG substitution was found in one patient, reported here for the first time in VUR. In silico results demonstrated alteration in two serine/arginine-rich (SR) protein-binding sites and two additional acceptor sites. The ROBO2 gene sequence was found to contain 25.9% transposable elements.ROBO2 variants were not found to be associated with nonsyndromic VUR or VUR-RHD, providing further evidence for genetic heterogeneity. The role of transposable elements in ROBO2 gene expression in CAKUT needs further investigation since they are generally considered to be mutagens.

Background: Increased plasma Urotensin II (UII) levels have been found in adults with renal diseases. Studies in children are scarce. The objective of the study is to estimate plasma UII levels in subjects with chronic kidney disease (CKD) stages 3 to 5 and renal transplant recipients (RTR). In addition, the correlation of UII with anthropometric features and biochemical parameters was assessed. Methods: Fifty-four subjects, aged 3 to 20 years old, 23 with CKD, 13 with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) and 18 RTR were enrolled. A detailed clinical evaluation was performed. Biochemical parameters of renal and liver function were measured. Plasma UII levels were measured in all patients and in 117 healthy controls, using a high sensitive enzyme immunoassay (EIA) kit. All data were analyzed using STATA™ (Version 10.1). Results: Median UII and mean log-transformed UII levels were significantly higher in CKD and RTR patients compared to healthy subjects (p < 0.001). HD patients had higher but not statistically significant UII and log-UII levels than controls. UII levels increased significantly at the end of the HD session and were higher than controls and in line to those of other patients. The geometric scores of UII in HD (before dialysis), CKD and RTR patients increased respectively by 42, 136 and 164% in comparison with controls. Metabolic acidosis was associated with statistical significant change in log-UII levels (p = 0.001). Patients with metabolic acidosis had an increase in UII concentration by 76% compared to those without acidosis. Conclusions: Children and adolescents with CKD, particularly those who are not on HD and RTR, have significantly higher levels of UII than healthy subjects. UII levels increase significantly at the end of the HD session. The presence of metabolic acidosis affects significantly plasma UII levels. © 2017 The Author(s).

Immune thrombocytopenia (ITP) in children is usually a benign, self-limiting disorder. An acute Epstein-Barr virus (EBV) infection usually causes atypical lymphocytosis and mild decrease in platelets. Severe thrombocytopenia is an extremely rare complication. Anti-D immunoglobulin has been used for treatment of ITP in Rh(D)-positive nonsplenectomized patients. Severe hemolysis and acute renal failure are extremely rare complications that may be aggravated by the presence of an acute EBV infection. It is believed that anti-D immunoglobulin triggers an unusual virus-induced immune response causing hemolysis. We present a 4-year-old girl with ITP caused by an acute EBV infection that developed acute kidney injury following treatment with anti-D immunoglobulin. The patient recovered completely from thrombocytopenia and renal dysfunction. Intravascular hemolysis and acute kidney injury are consistent with anti-D immunoglobulin mechanism of action. Pediatric patients treated with anti-D immunoglobulin for ITP should be closely monitored for signs and symptoms of hemolysis that may be aggravated by the presence of EBV infection leading to impaired renal function.

Mutations in the NPHS2 gene, encoding podocin, are a major cause of autosomal-recessive steroid-resistant nephrotic syndrome (SRNS) in childhood, accounting for up to 30% of sporadic and 20-40% of familial cases. Among 22 Greek children with a clinical diagnosis of SRNS, mutation analysis was performed in all eight NPHS2 gene exons, using denaturing gradient gel electrophoresis and DNA sequencing. The frequency of all nucleotide variations found in patients was also evaluated in 100 unrelated samples (18-30 years) with no known history of nephrotic disease. Three pathogenic genotypes (R138Q/R138Q, R229Q/A295T, and R168H/R168H) accounted for 3/14 (21%) of sporadic patients; the A295T mutation in exon 8 (c.883G>A) is novel and predicted in silico to be pathogenic. Among the familial cases, a single patient was heterozygous for R229Q. Several known polymorphisms were found, including the in cis variants IVS3-46C>T plus IVS3-21C>T, IVS7+7A>G A and exonic variants S96S (c.288C>T), A318A (c.954T>C), and L346L (c.1038A>G), with allele frequencies comparable to those in other populations. A novel substitution (IVS3-17C>T) was found in two related patients, but in no controls. In conclusion, podocin mutations do not appear to be a major cause of SRNS in Greek children, although the study cohort was small. However, NPHS2 gene analysis could still be considered in Greek SRNS patients to support appropriate management. The present study also contributes potentially useful observations for the clinical management of SRNS patients.

Οι συγγενείς ανωμαλίες του ουροποιητικού συστήματος ανευρίσκονται περίπου στο 0,5% όλων των κυήσεων και αποτελούν την πλέον συχνή αιτία τελικού σταδίου χρόνιας νεφρικής νόσου στα βρέφη και μικρά παιδιά. Περίπου το 30-40% των παιδιών με χρόνια νεφρική ανεπάρκεια ή τελικού σταδίου νεφρική ανεπάρκεια εμφανίζουν συγγενείς ανωμαλίες του ουροποιητικού. Από τις πιο συχνές είναι η κυστεοουρητηρική παλινδρόμηση (ΚΟΠ), η οποία συχνά συνοδεύεται από νεφρική υποπλασία/δυσπλασία (ΝΥΔ). Έως σήμερα η κληρονομικότητα και η παθογένεια αυτών των ανωμαλιών δεν έχει εξακριβωθεί. Το γονίδιο ROBO2 συμμετέχει στο αρχικό στάδιο της νεφρογένεσης που χαρακτηρίζεται από την επαγωγή ανάπτυξης της ουρητηρικής καταβολής (ΟΚ). Ωστόσο, δεν υπάρχει ομοφωνία στη διεθνή βιβλιογραφία σχετικά με την συμμετοχή αυτού του γονιδίου στην παθογένεια της ΚΟΠ.ΣκοπόςΟ σκοπός της διδακτορικής διατριβής είναι ο έλεγχος για την ύπαρξη μεταλλάξεων του γονιδίου ROBO2 σε παιδιά με ΚΟΠ και ΚΟΠ-ΝΥΔ. Επιπλέον ελέγχθηκαν in silico παράγοντες που μπορούν να επηρεάσουν επιγενετικά την έκφραση του γονιδίου. Υλικά και μέθοδοι Ελέγχθηκαν για νουκλεοτιδικές αλλαγές 103 παιδιατρικοί ασθενείς: 65 με ΚΟΠ (10 με οικογενή ΚΟΠ) και 38 με ΚΟΠ-ΝΥΔ. Επιπλέον ελέγχθηκαν 200 παιδιά παρόμοιας ηλικίας και φύλου με τους ασθενείς που αποτέλεσαν την ομάδα ελέγχου.Η ανάλυση στους ασθενείς πραγματοποιήθηκε με τις μεθόδους SSCP (Single Strand Conformation Polymorphism) ή MRF-SSCP (Multiple Restriction Fragment-SSCP), σε δύο διαφορετικές συνθήκες. Στα δείγματα που τα πρότυπα ζωνώσεων απέκλιναν από το φυσιολογικό, πραγματοποιήθηκε ανάλυση αλληλουχίας DNA (DNA sequencing). Η ομάδα ελέγχου ελέγχθηκε με περιοριστικές ενδονουκλεάσες ή με MRF-SSCP. Πραγματοποιήθηκε στατιστική (χ2 τέστ) και in silico ανάλυση για τις νουκλεοτιδικές αλλαγές που βρέθηκαν (ESEfinder και SplicePort). In silico ανάλυση πραγματοποιήθηκε επίσης για την περιεκτικότητα του γονιδίου σε CpG νησίδες (EMBOSS CpGPlot), την ομολογία του με miRNAs (miRBase) και την περιεκτικότητα του σε μεταθετά στοιχεία (UCSC Genome Bioinformatics, RepeatMasker).Αποτελέσματα Από την ανάλυση του γονιδίου, εντοπίστηκαν δύο πολυμορφισμοί: o IVS1-53G>A (rs9874095) και ο IVS5-31A>G (rs76571990). Για τον IVS1-53, το χ2 τεστ έδειξε στατιστικά σημαντική διαφορά υπέρ των μαρτύρων και η in silico ανάλυση έδειξε ότι δεν επηρεάζεται η αντίστοιχη περιοχή ματίσματος. Ο IVS5-31 ο οποίος αναφέρεται για πρώτη φορά στη διεθνή βιβλιογραφία, παρόλο που είναι καταγεγραμμένος στη βάση δεδομένων, βρέθηκε μόνο σε έναν ασθενή. Τα in silico αποτελέσματα για την επίδραση του στο μάτισμα του mRNA έδειξαν αλλαγή της σύνδεσης δύο SR πρωτεϊνών (ESEfinder) και δύο επιπλέον αλληλουχίες δέκτες (SplicePort), επομένως πιθανότατα αυτός ο πολυμορφισμός επηρεάζει το μάτισμα. Όσο αφορά την περιεκτικότητα του γονιδίου σε CpG νησίδες φέρει συνολικά οκτώ, μεγέθους >200 νουκλεοτίδια. Η αλληλουχία του ROBO2 έχει ομολογία με 17 ώριμα και 60 ανώριμα miRNAs. Μεγαλύτερη βαθμολογία και e-value10 νουκλεοτίδια. Η περιεκτικότητα του γονιδίου ROBO2 σε μεταθετά στοιχεία είναι 25,9% συμπεριλαμβανομένου των DNA τρανσποζονίων (4,55%), τα οποία όμως μέχρι σήμερα δεν έχει βρεθεί ότι συμμετέχουν σε κάποια βιολογική διεργασία. ΣυμπεράσματαΟι νουκλεοτιδικές αλλαγές του γονιδίου ROBO2 δε βρέθηκε να είναι υπεύθυνες για την εμφάνιση ΚΟΠ ή ΚΟΠ-ΝΥΔ στον πληθυσμό της μελέτης, ενισχύοντας την υποκείμενη γενετική ετερογένεια αυτών των νοσημάτων. Αν και προηγούμενες μελέτες έχουν δείξει ότι μεταλλάξεις του γονιδίου ROBO2 συσχετίζονται με την παρουσία ΚΟΠ, η παρούσα μελέτη δεν επιβεβαίωσε μια τέτοια συσχέτιση, υπογραμμίζοντας το γεγονός ότι η ΚΟΠ και η ΚΟΠ-ΝΥΔ είναι πολυπαραγοντικά νοσήματα. Ωστόσο, εκτός από τις αλλαγές στη αλληλουχία του DNA, η έκφραση του γονιδίου μπορεί να επηρεαστεί επιγενετικά από παράγοντες όπως είναι η μεθυλίωση, μέσω των CpG νησίδων, τα miRNAs ή τα μεταθετά στοιχεία. Από τα αποτελέσματα της μελέτης βρέθηκε ότι το γονίδιο ROBO2 είναι πιθανό να επηρεάζεται από αυτούς τους παράγοντες, καθώς (1) περιέχει οκτώ CpG νησίδες, (2) έχει ομολογία με υψηλή στοίχιση με 3 ώριμα miRNAs και με μικρότερη με 25 ανώριμα miRNAs και (3) το 21,35% της αλληλουχίας του είναι μεταθετά στοιχεία. Αυτοί οι παράγοντες ρύθμισης είναι πιθανό να μειώνουν την έκφραση του γονιδίου, ή να το αποσιωπούν, και έτσι να συμβάλουν στην εμφάνιση των ανωμαλιών που μελετήθηκαν, παρά την απουσία συγκεκριμένων νουκλεοτιδικών αλλαγών. Συνολικά, από τα αποτελέσματα φαίνεται ότι η προσέγγιση των συγγενών ανωμαλιών του ουροποιητικού στον άνθρωπο είναι εξαιρετικά δύσκολη και θα πρέπει να επικεντρωθεί σε πιο ολοκληρωμένα μοντέλα μελέτης, με κυτταρικές σειρές ή όπου είναι δυνατόν να μελετηθεί ιστός από νεφρικές βιοψίες.

Safety and immunogenicity of a booster dose of 7-valent pneumococcal conjugate vaccine (PCV7) were evaluated in 29 patients with idiopathic nephrotic syndrome (INS), who had been primed 12 months earlier with one dose of PCV7. PCV7 was not associated with increased risk of INS relapse (RR = 0.77, p = 0.8) and serotype-specific antibodies increased in all subjects at 1 month (p < 0.01). The quantitative characteristics of immune response and the effect of treatment with mycophenolate mofetil and/or cyclosporine A following booster PCV7 were similar with primary response. Additional PCV7 doses could be safely given in children with INS to increase circulating antibodies above the protective threshold. (C) 2014 Elsevier Ltd. All rights reserved.

Immune thrombocytopenia (ITP) in children is usually a benign, self-limiting disorder. An acute Epstein-Barr virus (EBV) infection usually causes atypical lymphocytosis and mild decrease in platelets. Severe thrombocytopenia is an extremely rare complication. Anti-D immunoglobulin has been used for treatment of ITP in Rh(D)-positive nonsplenectomized patients. Severe hemolysis and acute renal failure are extremely rare complications that may be aggravated by the presence of an acute EBV infection. It is believed that anti-D immunoglobulin triggers an unusual virus-induced immune response causing hemolysis. We present a 4-year-old girl with ITP caused by an acute EBV infection that developed acute kidney injury following treatment with anti-D immunoglobulin. The patient recovered completely from thrombocytopenia and renal dysfunction. Intravascular hemolysis and acute kidney injury are consistent with anti-D immunoglobulin mechanism of action. Pediatric patients treated with anti-D immunoglobulin for ITP should be closely monitored for signs and symptoms of hemolysis that may be aggravated by the presence of EBV infection leading to impaired renal function. Copyright © 2013 Lippincott Williams & Wilkins.

Safety, immunogenicity and kinetics of 7-valent pneumococcal-conjugate vaccine (PCV7) immune response were evaluated in 33 children with idiopathic nephrotic syndrome (INS) and 16 controls. PCV7 was not associated with increased risk of relapse (RR=0.80, p=0.61). Serotype (PS)-specific antibodies increased in all subjects at 1 month (p

Mutations in the Wilms' tumor suppressor gene 1 (WT1), most commonly within exons 8 or 9 or intron 9, are found in cases with the overlapping conditions of Denys-Drash and Frasier syndromes, as well as in patients with steroid-resistant nephrotic syndrome (SRNS). This study investigated the presence of WT1 gene mutations in cases with childhood SRNS, along with an evaluation of their clinical outcome. Twenty-seven Greek children with sporadic (19 cases) and familial (8 cases) SRNS were tested. Four phenotypically female patients with sporadic SRNS were found to carry de novo WT1 mutations, including two cases with p.R394W, and one case each with p.R366H, or n.1228+5G>A. Karyotype analysis found 46XX in three cases, but 46XY in one. No phenotype-genotype correlations were apparent in the WT1 gene positive cases since their clinical presentation varied broadly. Interestingly, one patient with a pathological WT1 nucleotide variation responded fully to combined therapy with cyclosporine A and corticosteroids. This study further illustrates that investigation of WT1 gene mutations is clinically useful to support definitive diagnosis in children presenting with SRNS in order to direct the most appropriate clinical management.

Mutations in the Wilms' tumor suppressor gene 1 (WT1), most commonly within exons 8 or 9 or intron 9, are found in cases with the overlapping conditions of Denys-Drash and Frasier syndromes, as well as in patients with steroid-resistant nephrotic syndrome (SRNS). This study investigated the presence of WT1 gene mutations in cases with childhood SRNS, along with an evaluation of their clinical outcome. Twenty-seven Greek children with sporadic (19 cases) and familial (8 cases) SRNS were tested. Four phenotypically female patients with sporadic SRNS were found to carry de novo WT1 mutations, including two cases with p.R394W, and one case each with p.R366H, or n.1228+5G>A. Karyotype analysis found 46XX in three cases, but 46XY in one. No phenotype-genotype correlations were apparent in the WT1 gene positive cases since their clinical presentation varied broadly. Interestingly, one patient with a pathological WT1 nucleotide variation responded fully to combined therapy with cyclosporine A and corticosteroids. This study further illustrates that investigation of WT1 gene mutations is clinically useful to support definitive diagnosis in children presenting with SRNS in order to direct the most appropriate clinical management. © 2011 Springer-Verlag.