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Background: X-linked hypophosphatemia (XLH) is a rare inherited phosphate-wasting disorder associated with bone and dental complications. Health-related quality of life (HRQoL) is reduced in XLH patients on conventional treatment with phosphate supplements and active vitamin D, while information on patients treated with burosumab is rare., Methods: HRQoL was assessed in 63 pediatric XLH patients participating in a prospective, observational study and patient registry in Germany using the KIDSCREEN-52 survey instrument and standardized qualitative interviews., Results: The median age of the XLH patients was 13.2 years (interquartile range 10.6 - 14.6). At the time of the survey, 55 (87%) patients received burosumab and 8 (13%) conventional treatment. Forty-six patients (84%) currently being treated with burosumab previously received conventional treatment. Overall, HRQoL was average compared to German reference values (mean ± SD: self-report, 53.36 ± 6.47; caregivers' proxy, 51.33 ± 7.15) and even slightly above average in some dimensions, including physical, mental, and social well-being. In general, XLH patients rated their own HRQoL higher than their caregivers. In qualitative interviews, patients and caregivers reported that, compared with conventional therapy, treatment with burosumab reduced stress, bone pain, and fatigue, improved physical health, and increased social acceptance by peers and the school environment., Conclusions: In this real-world study in pediatric XLH patients, HRQoL was average or even slightly above that of the general population, likely due to the fact that the vast majority of patients had their treatment modality switched from conventional treatment to burosumab resulting in improved physical health and well-being., (© 2024. The Author(s).)

Introduction: Hepatocyte nuclear factor 1-beta ( HNF1B ) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease., Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype ( HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m 2 ). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia., Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, P  < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POU h ) DNA-binding and transactivation domains rather than the POU-specific domain (POU s ) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), P  < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), P  = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia., Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POU s DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Context: Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking., Objective: To assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged <12 years) and adolescents (aged 12-18 years) with XLH., Design: Prospective national registry., Setting: Hospital clinics., Patients: A total of 93 patients with XLH (65 children, 28 adolescents)., Main Outcome Measures: Z scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months., Results: At baseline, patients showed hypophosphatemia (-4.4 SD), reduced TmP/GFR (-6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01)., Conclusions: In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rose propagation by cuttings is limited by substantial genotypic differences in adventitious root formation. To identify possible genetic factors causing these differences and to develop a marker for marker-assisted selection for high rooting ability, we phenotyped 95 cut and 95 garden rose genotypes in a hydroponic rooting system over 6 weeks. Data on rooting percentage after 3 to 6 weeks, root number, and root fresh mass were highly variable among genotypes and used in association mappings performed on genotypic information from the WagRhSNP 68 K Axiom SNP array for roses. GWAS analyses revealed only one significantly associated SNP for rooting percentage after 3 weeks. Nevertheless, prominent genomic regions/peaks were observed and further analysed for rooting percentage after 6 weeks, root number and root fresh mass. Some of the SNPs in these peak regions were associated with large effects on adventitious root formation traits. Very prominent were ten SNPs, which were all located in a putative phosphoinositide phosphatase SAC9 on chromosome 2 and showed very high effects on rooting percentage after 6 weeks of more than 40% difference between nulliplex and quadruplex genotypes. SAC9 was reported to be involved in the regulation of endocytosis and in combination with other members of the SAC gene family to regulate the translocation of auxin-efflux PIN proteins via the dephosphorylation of phosphoinositides. For one SNP within SAC9, a KASP marker was successfully derived and used to select genotypes with a homozygous allele configuration. Phenotyping these homozygous genotypes for adventitious root formation verified the SNP allele dosage effect on rooting. Hence, the presented KASP derived from a SNP located in SAC9 can be used for marker-assisted selection in breeding programs for high rooting ability in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wamhoff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background:  Probiotics are often viewed as an immunity enhancing agent. The objective of this study was to investigate whether oral administration of Escherichia coli Nissle 1917 reduces the number of infections, their duration, and severity in the first 24 months after parturition in healthy neonates., Subjects and Methods:  This prospective, confirmatory, randomised, double-blind, placebo-controlled study enrolled 567 healthy neonates from four German and two Polish sites. Neonates received 10e8 viable E. coli Nissle (n=283) or placebo (n=284) daily in the first week and every second day in week 2 and 3. After 6 and 12 months, the subjects received additional instillations on ten subsequent days. The overall efficacy was assessed by the number of infections per observation period., Results:  Incidence rates of infection, infection duration and severity showed no statistically significant difference between groups after 24 months. Post-hoc analyses, however, revealed a short-term benefit of E. coli Nissle four weeks after treatment start which became less pronounced after eight weeks. E. coli Nissle was safe and well tolerated., Conclusions:  A long-term effect after colonising the healthy neonate´s gut with E. coli Nissle to protect against infections could not be shown. Additional studies are needed to confirm a transitory, yet clinically significant role of probiotics in the first four weeks after parturition., Competing Interests: D. Olbertz received an investigator’s fee and reimbursements for two related congress presentations and associated travel from Ardeypharm GmbH; C. Wolff was employed by Ardeypharm GmbH for the duration of the study; M. Radke received consultancy fees in relation to the project from Ardeypharm GmbH. All authors received reimbursement of study-related expenditures from Ardeypharm GmbH., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

X-linked Alport syndrome (AS) caused by hemizygous disease-causing variants in COL4A5 primarily affects males. Females with a heterozygous state show a diverse phenotypic spectrum ranging from microscopic hematuria to end-stage kidney disease (ESKD) and extrarenal manifestations. In other X-linked diseases, skewed X-inactivation leads to preferential silencing of one X-chromosome and thus can determine the phenotype in females. We aimed to show a correlation between X-inactivation in blood and urine-derived renal cells and clinical phenotype of females with a heterozygous disease-causing variant in COL4A5 compared to healthy controls. A total of 56 females with a heterozygous disease-causing COL4A5 variant and a mean age of 31.6 ± 18.3 SD years were included in this study. A total of 94% had hematuria, 62% proteinuria >200 mg/day, yet only 7% had decreased eGFR. Using human androgen receptor assay X-inactivation was examined in blood cells of all 56 individuals, in urine-derived cells of 27 of these individuals and in all healthy controls. X-inactivation did not correlate with age of first manifestation, proteinuria or eGFR neither in blood, nor in urine. The degree of X-inactivation showed a moderate association with age, especially in urine-derived cells of the patient cohort ( rho = 0.403, p = 0.037). Determination of X-inactivation allelity revealed a shift of X-inactivation toward the COL4A5 variant bearing allele. This is the first study examining X-inactivation of urine-derived cells from female individuals with AS. A correlation between phenotype and X-inactivation could not be observed suspecting other genetic modifiers shaping the phenotype in female individuals with AS. The association of X-inactivation with age in urine-derived cells suggests an escape-mechanism inactivating the COL4A5 variant carrying allele in female individuals with AS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Günthner, Knipping, Jeruschke, Satanoskij, Lorenz-Depiereux, Hemmer, Braunisch, Riedhammer, Ćomić, Tönshoff, Tasic, Abazi-Emini, Nushi-Stavileci, Buiting, Gjorgjievski, Momirovska, Patzer, Kirschstein, Gross, Lungu, Weber, Renders, Heemann, Meitinger, Büscher and Hoefele.)

Infantile nephropathic cystinosis, due to impaired transport of cystine out of lysosomes, occurs with an incidence of 1 in 100-200,000 live births. It is characterized by renal Fanconi syndrome in the first year of life and glomerular dysfunction progression to end-stage kidney disease by approximately 10 years of age. Treatment with oral cysteamine therapy helps preserve glomerular function, but affected individuals eventually require kidney replacement therapy. This is because glomerular damage had already occurred by the time a child is diagnosed with cystinosis, typically in the second year of life. We performed a retrospective multicenter study to investigate the impact of initiating cysteamine treatment within the first 2 months of life in some infants and comparing two different levels of adherence in patients diagnosed at the typical age. We collected 3983 data points from 55 patients born between 1997 and 2020; 52 patients with 1592 data points could be further evaluated. These data were first analyzed by dividing the patient cohort into three groups: (i) standard treatment start with good adherence, (ii) standard treatment start with less good adherence, and (iii) early treatment start. At every age, mean estimated glomerular filtration rate (eGFR) was higher in early-treated patients than in later-treated patients. Second, a generalized additive mixed model (GAMM) was applied showing that patients with initiation of treatment before 2 months of age are expected to have a 34 ml/min/1.73 m 2 higher eGFR than patients with later treatment start while controlling for adherence and patients' age. These data strongly suggest that oral cysteamine treatment initiated within 2 months of birth preserves kidney function in infantile nephropathic cystinosis and provide evidence of the utility of newborn screening for this disease., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder resulting in progressive chronic kidney disease (CKD) and a variety of extrarenal manifestations. This orphan disease remains a challenge for patients, their families and health care providers. There is currently no comprehensive study on patients' clinical course in Germany and Austria., Methods: A retrospective cohort study including 74 patients at eleven centers of care was conducted. Data on time of diagnosis, CKD stage, leukocyte cystine levels (LCL), extrarenal manifestations, and treatment was collected from medical charts and subsequently analyzed using explorative statistics. Age at initiation of kidney replacement therapy (KRT) was evaluated by Kaplan-Meier analyses for different groups of patients., Results: Patients were diagnosed at a median age of 15 months (IQR: 10-29, range: 0-110), more recent year of birth was not associated with earlier diagnosis. Oral cystine-depleting therapy (i.e., cysteamine) was prescribed at a median dose of 1.26 g/m 2 per day (IQR: 1.03-1.48, range: 0.22-1.99). 69.2% of all 198 LCL measurements of 67 patients were within the desired target range (≤ 1 nmol cystine/mg protein). Median time-averaged LCLs per patient ( n = 65) amounted to 0.57 nmol cystine/mg protein (IQR: 0.33-0.98, range: 0.07-3.13) when considering only values at least 1 year after initiation of therapy. The overall median height of 242 measurements of 68 patients was at the 7 th percentile (IQR: 1-25, range: 1-99). 40.5% of the values were ≤ the 3 rd percentile. Patient sex and year of birth were not associated with age at initiation of KRT, but patients diagnosed before the age of 18 months required KRT significantly later than those patients diagnosed at the age of ≥ 18 months ( p = 0.033): median renal survival was 21 years (95% CI: 16, -) vs. 13 years (95% CI, 10, -), respectively., Conclusion: Early diagnosis and initiation of cystine depleting therapy is important for renal survival in children with INC. Cysteamine doses and LCL showed that treatment in this cohort met international standards although there is great interindividual variety. Patient growth and other aspects of the disease should be managed more effectively in the future., Competing Interests: DH received speaker fees and research support, CK and BT received speaker and advisory board fees from Chiesi. LPe, LW, and JO received speaker fees from Chiesi and Orphan Europe. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 O'Connell, Oh, Arbeiter, Büscher, Haffner, Kaufeld, Kurschat, Mache, Müller, Patzer, Weber, Tönshoff, Weitz, Hohenfellner and Pape.)

Background: Hereditary cystic kidney diseases such as nephronophthisis, polycystic kidney disease and Bardet-Biedl syndrome (BBS) are caused by a dysfunction of primary cilia. Cilia are involved in a variety of cellular functions and perceptions, with one of them being the sense of smell. Hyposmia is a typical feature found in patients with BBS. However, reports of olfactory dysfunction in other cystic kidney diseases are sparse. Here we provide a systematic survey on olfaction in a large cohort of patients displaying genetically determined renal ciliopathies., Methods: We performed a match-controlled systematic olfactory evaluation in a group of 75 patients with a defined genetic background using age adapted and validated odour identification tests., Results: Test results revealed a significant olfactory deficit in patients carrying TMEM67 variants (n=4), while all other genetic disorders causing nephronophthisis (n=25) or polycystic kidney disease (n=18) were not associated with an impaired sense of smell. Also in patients with BBS, olfactory performance was depending on the underlying molecular defect. While defects in the BBS1 gene (n=9) had no impact on the sense of smell, all other BBS gene disorders (n=19) were associated with significant hyposmia. Noteworthy, there was no correlation of the olfactory deficit with the level of renal impairment., Conclusion: Hyposmia is a part of the clinical spectrum of BBS and of other renal ciliopathies. Depending on the genetic background, clinicians should be aware of this subtle and so far underappreciated symptom when clinically assessing patients with BBS or TMEM67 gene variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4-15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.

Background: HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult., Methods: Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases., Results: Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of - 0.33 ml/min/1.73m 2 per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was - 2.8 ml/min/1.73m 2 (± 13.2), in the total cohort - 1.0 ml/min/1.73m 2 (±10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases., Conclusions: In most children, HNF1B nephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease.

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH., (Copyright © 2016 by the American Society of Nephrology.)

Background: The hereditary kidney disease Alport syndrome (AS) has become a treatable disease: intervention with angiotensin-converting enzyme (ACE)-inhibitors delays end stage renal failure by years. The efficiency of ACE inhibition depends on the onset of therapy-the earlier the better. Therefore, early diagnosis has become increasingly important. To date, robust diagnosis requires renal biopsy and/or expensive genetic analysis, which is mostly performed late after onset of the profound clinical symptoms of this progressive renal disease. Thus, disease biomarkers enabling low-invasive screening are urgently required., Methods: Fourteen potential proteomic candidate markers (proteins) identified in a previous study in sera from patients exhibiting manifest AS were evaluated in the plasma, serum, and urine collected from a cohort of 132 subjects, including patients with AS and other nephropathies and healthy controls. Quantitation was performed by immunoassays., Results: The serum and plasma levels of none of the 14 proteins evaluated were significantly different among the three groups and therefore could not be used to discriminate between the groups. In contrast, the levels of various biomarker combinations in the urine were significantly different between AS patients and healthy controls. Importantly, some combinations had the potential to discriminate between AS and other nephropathies., Conclusions: These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients.

Background: In patients with refractory steroid-sensitive nephrotic syndrome (SSNS), treatment with rituximab has shown encouraging results; however, long-term follow-up data are not available., Methods: We performed a retrospective analysis of 37 patients (25 boys) with steroid-dependent nephrotic syndrome who were treated with rituximab (375 mg/m(2) given weekly for one to four courses). Long-term follow-up data (>2 years, median 36, range 24-92.8 months) are available for 29 patients (12 boys)., Results: Twenty-six of 37 (70.3%) patients remained in remission after 12 months. Relapses occurred in 24 (64.8%) patients after a median of 9.6 (range 5.2-64.1) months. Time to first relapse was significantly shorter in patients receiving one or two compared to three or four initial infusions. In the 29 patients with long-term follow-up for >2 years, 12 (41%) patients remained in remission after the initial rituximab course for >24 months, 7 (24.1%) patients without further maintenance immunosuppression. Nineteen children received two to four repeated courses of rituximab increasing the total number of patients with long-term remission to 20 (69%), remission including 14 (48%) patients off immunosuppression. The proportion of patients with long-term remission was not related to the number of initial rituximab applications. No serious side effects were noted., Conclusion: Rituximab is an effective treatment option in the short- and long-term control of treatment refractory SSNS. Further controlled studies are needed to address optimal patient selection, dose and safety of rituximab infusions.

We report a male newborn presenting with sonographically normal kidneys, oligohydramnios during late pregnancy, and persisting anuric renal failure. Despite intensive treatment, the patient suffered from severe hypotension and died at the age of 4 weeks. At autopsy, kidneys were found to be normal; on histology, deranged renal structures, in particular proximal tubuli and vessels, were noted, leading to the diagnosis of renal tubular dysgenesis (RTD). The diagnosis was confirmed by 2 heterozygous nonsense mutations of the ACE gene. Because the recurrence rate of RTD is 25% for the autosomal recessive trait, knowledge and genetic diagnosis of the disease is important for the parents., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hereditary atypical hemolytic uremic syndrome (aHUS), a dramatic disease frequently leading to dialysis, is associated with germline mutations of the CFH, CD46, or CFI genes. After identification of the mutation in an affected aHUS patient, single-site gene testing of relatives is the preventive care perspective. However, clinical data for family counselling are scarce. From the German-Speaking-Countries-aHUS-Registry, 33 index patients with mutations were approached for permission to offer relatives screening for their family-specific mutations and to obtain demographic and clinical data. Mutation screening was performed using direct sequencing. Age-adjusted penetrance of aHUS was calculated for each gene in index cases and in mutation-positive relatives. Sixty-one relatives comprising 41 parents and 20 other relatives were enrolled and mutations detected in 31/61. In total, 40 research participants had germline mutations in CFH, 19 in CD46 and in 6 CFI. Penetrance at age 40 was markedly reduced in mutation-positive relatives compared to index patients overall with 10% versus 67% (P < 0.001); 6% vs. 67% (P < 0.001) in CFH mutation carriers and 21% vs. 70% (P= 0.003) in CD46 mutation carriers. Age-adjusted penetrance for hereditary aHUS is important to understand the disease, and if replicated in the future, for genetic counselling., (© 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.)

Atypical hemolytic uremic syndrome (aHUS) is caused by several susceptibility genes. A registry including analyses of susceptibility genes, familial occurrence and genotype-phenotype correlation should provide classification insights. Registry data of 187 unrelated index patients included age at onset, gender, family history, relapse of aHUS and potentially triggering conditions. Mutation analyses were performed in the genes CFH, CD46 and CFI and in the six potential susceptibility genes, FHR1 to FHR5 and C4BP. Germline mutations were identified in 17% of the index cases; 12% in CFH, 3% in CD46 and 2% in CFI. Twenty-nine patients had heterozygous mutations and one each had a homozygous and compound heterozygous mutation. Mutations were not found in the genes FHR1-5 and C4BP. In 40% of the patients with familial HUS a mutation was found. Penetrance by age 45 was 50% among carriers of any mutation including results of relatives of mutation-positive index cases. The only risk factor for a mutation was family history of HUS (p = 0.02). Penetrance of aHUS in carriers of mutations is not complete. Occurrence of homo- and heterozygous mutations in the same gene suggests that the number of necessary DNA variants remains unclear. Among clinical information only familial occurrence predicts a mutation.

Many different drugs and agents may cause nephrotoxic acute kidney injury (AKI) in children. Predisposing factors such as age, pharmacogenetics, underlying disease, the dosage of the toxin, and concomitant medication determine and influence the severity of nephrotoxic insult. In childhood AKI, incidence, prevalence, and etiology are not well defined. Pediatric retrospective studies have reported incidences of AKI in pediatric intensive care units (PICU) of between 8% and 30%. It is widely recognized that neonates have higher rates of AKI, especially following cardiac surgery, severe asphyxia, or premature birth. The only two prospective studies in children found incidence rates of 4.5% and 2.5% of AKI in children admitted to PICU, respectively. Nephrotoxic drugs account for about 16% of all AKIs most commonly associated with AKI in older children and adolescents. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, amphotericin B, antiviral agents, angiotensin-converting enzyme (ACE) inhibitors, calcineurin inhibitors, radiocontrast media, and cytostatics are the most important drugs to indicate AKI as significant risk factor in children. Direct pathophysiological mechanisms of nephrotoxicity include constriction of intrarenal vessels, acute tubular necrosis, acute interstitial nephritis, and-more infrequently-tubular obstruction. Furthermore, AKI may also be caused indirectly by rhabdomyolysis. Frequent therapeutic measures consist of avoiding dehydration and concomitant nephrotoxic medication, especially in children with preexisting impaired renal function.